Dipeptidyl peptidase-iv inhibitors

ABSTRACT

The present invention relates generally to pyrrolidine and thiazolidine DPP-IV inhibitor compounds. The present invention also provides synthetic methods for preparation of such compounds, methods of inhibiting DPP-IV using such compounds and pharmaceutical formulations containing them for treatment of DPP-IV mediated diseases, in particular, Type-2 diabetes.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.11/409,481, filed Apr. 21, 2006, now U.S. Pat. No. 7,553,861, the entirecontents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to pyrrolidine and thiazolidine-basedinhibitors of dipeptidyl peptidase-IV (DPP-IV) and to methods fortreating diabetes, particularly Type-2 diabetes as well as impairedglucose tolerance, impaired glucose homeostasis and complicationsassociated with diabetes by inhibiting DPP-IV with such cyclic amido andcyclic ureido pyrrolidine and thiazolidine inhibitors.

BACKGROUND OF THE INVENTION

Diabetes results from the occurrence of one or more of several causativefactors, and is characterized by an abnormal elevation in levels ofplasma glucose (hyperglycemia). Persistent or uncontrolled hyperglycemiaresults in an increased probability of premature morbidity andmortality. Abnormal glucose homeostasis is usually associated withchanges in the lipid, lipoprotein and apolipoprotein metabolism, or dueto other metabolic and hemodynamic diseases.

Patients afflicted with Type-2 diabetes mellitus or noninsulin dependentdiabetes mellitus (NIDDM), are especially at increased risk of sufferingfrom macrovascular and microvascular complications, including coronaryheart disease, stroke, peripheral vascular disease, hypertension,nepHropathy, neuropathy and retinopathy. Therapeutic control of glucosehomeostasis, lipid metabolism and hypertension are critical in theclinical management and treatment of Type-2 diabetes mellitus.

The currently available therapeutics for treating available Type-2diabetes, although effective, have recognized limitations. Compoundsbased on sulfonylureas (e.g. tolbutamide, glipizide, etc.), whichstimulate the pancreatic beta-cells to secrete more insulin, are limitedby the development of inhibitor resistant tissues, causing them tobecome inefficient or ineffective, even at high doses. Biguanidecompounds, on the other hand, increase insulin sensitivity so as tocause correction of hyperglycemia to some extent. However, clinicallyused biguanides such as phenformin and metformin can induce side-effectssuch as lactic acidosis, nausea and diarrhea.

The more recent glitazone-type compounds (i.e.5-benzylthiazolidine-2,4-diones) substantially increase insulinsensitivity in muscle, liver and adipose tissue resulting in eitherpartial or complete correction of the elevated plasma levels of glucosewithout occurrence of hypoglycemia. Currently used glitazones areagonists of the peroxisome proliferator activated receptor (PPAR), whichis attributed to be responsible for their improved insulinsensitization. However, serious side effects (e.g. liver toxicity) havebeen known to occur with some glitazones such as, for example,troglitazone. Compounds that are inhibitors of the dipeptidylpeptidase-IV (“DPP-IV”, “DPP-4” or “DP-IV”) enzyme are also underinvestigation as drugs that may be useful in the treatment of diabetes,and particularly Type-2 diabetes. See for example, WO 97/40832, WO98/19998, and U.S. Pat. No. 5,939,560.

DPP-IV is a membrane bound non-classical serine aminodipeptidase whichis located in a variety of tissues (intestine, liver, lung, kidney) aswell as on circulating T-lymphocytes (where the enzyme is known asCD-26). It is responsible for the metabolic cleavage of certainendogenous peptides (GLP-1(7-36), glucagon) in vivo and has demonstratedproteolytic activity against a variety of other peptides (e.g. GHRH,NPY, GLP-2, VIP) in vitro.

The usefulness of DPP-IV inhibitors in the treatment of Type-2 diabetesis based on the fact that DPP-IV in vivo readily inactivates glucagonlike peptide-1 (GLP-1) and gastric inhibitory peptide (GIP). GLP-1(7-36) is a 29 amino-acid peptide derived by post-translationalprocessing of proglucagon in the small intestine. GLP-1(7-36) hasmultiple actions in vivo including the stimulation of insulin secretion,inhibition of glucagon secretion, the promotion of satiety, and theslowing of gastric emptying. Based on its physiological profile, theactions of GLP-1(7-36) are expected to be beneficial in the preventionand treatment of Type-2 diabetes, and potentially obesity. To supportthis claim, exogenous administration of GLP-1(7-36) (continuousinfusion) in diabetic patients has demonstrated efficacy in this patientpopulation. GLP-1(7-36) is degraded rapidly in vivo and has been shownto have a short half-life in vivo (t1/2 of about 1.5 min). Based on astudy of genetically bred DPP-IV KO mice and on in vivo/in vitro studieswith selective DPP-IV inhibitors, DPP-IV has been shown to be theprimary degrading enzyme of GLP-1(7-36) in vivo. GLP-1(7-36) is degradedby DPP-IV efficiently to GLP-1(9-36), which has been speculated to actas a physiological antagonist to GLP-1(7-36). Inhibition of DPP-IV invivo should, therefore, potentiate endogenous levels of GLP-1(7-36) andattenuate formation of its antagonist GLP-1(9-36) and serve toameliorate the diabetic condition.

GLP-1 and GIP are incretins that are produced upon ingestion of food,and which stimulate production of insulin. Inhibition of DPP-IV causesdecreased inactivation of the incretins, which in turn, results in anincrease in their effectiveness in stimulating pancreatic production ofinsulin. DPP-IV inhibition therefore, results in an increase in thelevel of serum insulin. Since the incretins are produced uponconsumption of food only, DPP-IV inhibition is not expected to increaseinsulin levels when not required, thereby precluding excessive loweringof blood sugar (hypoglycemia). Inhibition of DPP-IV, is therefore, isexpected to increase insulin levels without increasing the risk ofhypoglycemia, thereby lowering deleterious side effects associated withcurrently used insulin secretagogues. Although DPP-IV inhibitors havenot been studied extensively as therapeutics for diseases other thandiabetes, they are expected to have other potential therapeuticutilities.

SUMMARY OF THE INVENTION

The present invention relates to a class of pyrrolidine-based inhibitorsof dipeptidyl peptidase-IV (DPP-IV). In particular, the presentinvention provides a new class of pyrrolidine and thiazolidine DPP-IVinhibiting compounds (“DPP-IV inhibitors”).

One aspect of the present invention includes a compound of formula (I):

A-B-D  (I)

and all stereoisomers, diastereomers, racemic mixtures andpharmaceutically acceptable salts thereof and all polymorphs; wherein Ais:

wherein

E and G are independently 6-membered aryl, or 5-membered heteroaryl or6-membered heteroaryl;

E may be substituted with one or more R¹ groups;

G may be substituted with one or more R² groups;

X and Y are divalent and are each independently: a bond, CR⁴R⁵, O, NR⁴,S, S═O, S(═O)₂, C(═O), (C═O)N(R⁴), S(═O)₂N(R⁴), C═N—OR⁴,—C(R⁴R⁵)C(R⁴R⁵)—, —C(R⁴R⁵) C(R⁴R⁵)C(R⁴R⁵)—,—C(R⁴R⁵)C(R⁴R⁵)C(R⁴R⁵)C(R⁴R⁵)—, —C(R⁴)═C(R⁵)—, —C(R⁴R⁵)NR⁴—, —C(R⁴R⁵)O—,—C(R⁴R⁵)S(═O)_(t)—, —(C═O)O—, —(C═NR^(a))N(R⁴)—, —(C═NR^(a))—,N(C═O)NR⁴NR⁵, N(C═O)R⁴, N(C═O)OR⁴, NS(═O)₂NR⁴NR⁵, NS(═O)₂R⁴; or aryl,heteroaryl, cycloalkyl or heterocyclic ring, all of which may beoptionally substituted;

R¹ and R² are each independently: halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂,CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall of which may be optionally substituted;

R³ is absent or is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴,CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵,NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocyclyl, heterocycloalkylalkyl,haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl and aminoalkyl all of which may be optionally substituted;

R^(a) is hydrogen, CN, NO₂, alkyl, haloalkyl, S(O)_(t)NR⁴R⁵, S(O)_(t)R⁴,C(O)OR⁴, C(O)R⁴, or C(O)NR⁴R⁵; each occurrence of R⁴, R⁵, R²⁰ and R²¹are each independently: hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkynyl, aryl,heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl, wherein alkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl,heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl and aminoalkyl are all optionally substituted, or R⁴ andR⁵ when taken together with the nitrogen to which they are attachedcomplete a 3- to 8-membered ring containing carbon atoms and mayoptionally contain a heteroatom selected from O, S, or NR⁵⁰ and the 3-to 8-membered ring may be optionally substituted;

R⁵⁰ is, in each occurrence, R²⁰, CN, NO₂, S(O)_(t)NR²⁰R²¹, S(O)_(t)R²⁰,C(O)OR²⁰, C(O)R²⁰C(═NR^(a))NR²⁰R²¹, C(═NR²⁰)NR²¹R^(a), C(═NOR²⁰)R²¹ orC(O)NR²⁰R²¹;

each occurrence of R⁷ and R⁸ are each independently: halogen, CF₃, COR⁴,OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴,SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵,(C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₁-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylare all optionally substituted;

R⁹ is H or C₁₋₆ alkyl;

R¹⁰ is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵,CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵,NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₁-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, B(OH)₂, alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl and aminoalkyl are all optionally substituted;

R¹¹ and R¹² are each independently: halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂,CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylare all optionally substituted;

R^(13a) and R^(13b) are each independently R⁵ or together are ═O;

R^(14a) and R^(14b) are each independently R⁵ or together are ═O;

R^(13c) and R^(14c) are each independently R⁵;

Q^(a) is CH or N;

U is —C(O)—, —C(═NR⁴)—, —(CR⁴R⁵—)_(p), NR⁵⁰, S(═O)₂, C(═O), (C═O)N(R⁴),N(R⁴)(C═O), S(═O)₂N(R⁴), N(R⁴)S(═O)₂, C═N—OR⁴, —C(R⁴)═C(R⁵)—,—C(R⁴R⁵)_(p)NR⁵⁰—, N(R⁵⁰)C(R⁴R⁵)_(p), —O—C(R⁴R⁵)—, —C(R⁴R⁵)S(═O)_(t)—,—(C═O)O—, —(C═NR^(a))N(R⁴)—, —(C═NR^(a))—, N(C═O)NR NR⁵, N(C═O)R⁴,N(C═O)OR^(a), NS(═O)₂NR⁴NR⁴, NS(═O)₂R⁴, or an optionally substitutedaryl, heteroaryl, cycloalkyl or heterocyclic ring, all of which may beoptionally substituted;

W is —CH₂—, —S—, —CHF— or —CF₂—;

Z is C or N;

m is 1, or 2;

n is 0, 1, or 2;

p is 0 to 6;

q is 0 to 6; and

t is 0, 1, or 2.

Another aspect of the present invention includes a method of preparing acompound of the following formula:

comprising (a) coupling prolinamide with fumarylchloride to provide acompound of the following formula:

(b) dehydrating the carboxamides of the compound from step (a) to cyanoto provide a compound of formula:

and (c) cleaving the C═C bond with an oxidizing agent either: (1) in thepresence of methanol, and then adding a reducing agent to the reactionmixture, or (2) and reacting the cleavage products with a reducing agentand subsequently adding methanol to the cleavage product mixture.

A further aspect of the present invention provides a method of preparinga compound of the following formula:

comprising: (a) coupling a compound of formula:

with fumaryl chloride to provide a compound of formula

(b) dehydrating the carboxamide in the compound from step (a) to providea compound of formula:

and (c) cleaving the C═C bond with an oxidizing agent either: (1) in thepresence of methanol, and then adding a reducing agent to the reactionmixture, or (2) and reacting the cleavage products with a reducing agentand subsequently adding methanol to the cleavage product mixture.

Another aspect of the present invention provides a compound of formula Acompound of formula (I):

A-B-D  (I)

wherein A is:

B is:

and

D is:

wherein

E and G are independently selected from 6-membered aryl, 5-memberedheteroaryl, 6-membered heteroaryl, and 5-6-membered saturated orpartially saturated carbocyclic or heterocyclic rings;

E may be substituted with one or more R¹ groups;

G may be substituted with one or more R² groups;

R¹ and R² are independently: halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN,SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylare all optionally substituted;

R³ is absent or is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴,CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵,NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylare all optionally substituted;

R^(a) is hydrogen, CN, NO₂, alkyl, haloalkyl, S(O)_(t)NR⁴R⁵, S(O)_(t)R⁴,C(O)OR⁴, C(O)R⁴, or C(O)NR⁴R⁵;

each occurrence of R⁴, R⁵, R²⁰ and R²¹ are each independently: hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl,heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl andaminoalkyl are all optionally substituted, or R⁴ and R⁵ when takentogether with the nitrogen to which they are attached complete a 3- to8-membered ring containing carbon atoms and may be optionally containinga heteroatom selected from O, S, or NR⁵⁰ and the 3- to 8-membered ringmay be optionally substituted;

R⁵⁰ is, in each occurrence, R²⁰, CN, NO₂, S(O)_(t)NR²⁰R²¹, S(O)_(t)R²⁰,C(O)OR²⁰, C(O)R²⁰C(═NR^(a))NR²⁰R²¹, C(═NR²⁰)NR²¹R^(a), C(═NOR²⁰)R²¹ orC(O)NR²⁰R²¹;

each occurrence of R⁷ and R⁸ are each independently: halogen, CF₃, COR⁴,OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴,SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵,(C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₁-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall may be optionally substituted;

R⁹ is H or C₁₋₆alkyl;

R¹⁰ is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵,CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵,NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, B(OH)₂, alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl and aminoalkyl all may be optionally substituted;

R¹¹ and R¹² are each independently: halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂,CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (CO—C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall may be optionally substituted;

R^(13a) and R^(13b) are each independently R⁵ or together are ═O;

R^(14a) and R^(14b) are each independently R⁵ or together are ═O;

R^(13c) and R^(14c) are each independently R⁵;

Q^(a) is CH or N;

U is —C(O)—, —C(═NR⁴)—, —(CR⁴R⁵—)_(p), NR⁵⁰, S(═O)₂, C(═O), (C═O)N(R⁴),N(R⁴)(C═O), S(═O)₂N(R⁴), N(R⁴)S(═O)₂, C═N—OR⁴, —C(R⁴)═C(R⁵)—,—C(R⁴R⁵)_(p)NR⁵⁰—, N(R⁵⁰)C(R⁴R⁵)_(p)—, —O—C(R⁴R⁵)—, —C(R⁴R⁵)S(═O)_(t)—,—(C═O)O—, —(C═NR^(a))N(R⁴)—, —(C═NR^(a))—, N(C═O)NR⁴NR⁵, N(C═O)R⁴,N(C═O)OR⁴, NS(═O)₂NR⁴NR⁵, NS(═O)₂R⁴, or an optionally substituted aryl,heteroaryl, cycloalkyl or heterocyclic ring, all of which may beoptionally substituted;

W is —CH₂—, —S—, —CHF— or —CF₂—;

Z is C or N;

m is 1, or 2;

n is 0, 1, or 2;

p is 0 to 6;

q is 0 to 6; and

t is 0, 1, or 2

wherein: when E and G are both phenyl either:

(1) at least one of R¹ or R² is present and is:

CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂₀R⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵,S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵,(C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, (C₅₋₂₀)alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl and aminoalkyl are all optionally substituted; and whereinOR⁴ is alkoxy, OR⁴ is (C₅₋₂₀) alkoxy; or (2) and when B is (b) R⁷ and R⁸are not selected from hydrogen, hydroxy, hydroxymethyl, and phenyl; or(3) and when B is (b) or (f), R9 is: C₁₋₆ alkyl.

Another aspect of the present invention provides a compound of formula Acompound of formula (I):

A-B-D  (I)

wherein A is:

B is:

and

D is:

wherein

E, G, and M include a three ring system wherein M shares two carbonatoms with each of E and G;

E, G and M are each independently selected from a 5-7-membered saturatedor partially saturated carbocyclic ring, a 5-7 membered saturated orpartially saturated heterocyclic ring, a 5-6-membered aromatic ring, anda 5-6-membered heteroaromatic ring;

E may be substituted with one or more R¹ groups;

G may be substituted with one or more R² groups;

R¹ and R² are independently: halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN,SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylare all optionally substituted;

R³ is absent or is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴,CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵,NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)t—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylare all optionally substituted;

R^(a) is hydrogen, CN, NO₂, alkyl, haloalkyl, S(O)_(t)NR⁴R⁵, S(O)_(t)R⁴,C(O)OR⁴, C(O)R⁴, or C(O)NR⁴R⁵;

each occurrence of R⁴, R⁵, R²⁰ and R²¹ are each independently: hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl,heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl andaminoalkyl are all optionally substituted, or R⁴ and R⁵ when takentogether with the nitrogen to which they are attached complete a 3- to8-membered ring containing carbon atoms and may be optionally containinga heteroatom selected from O, S, or NR⁵⁰ and the 3- to 8-membered ringmay be optionally substituted;

R⁵⁰ is, in each occurrence, R²⁰, CN, NO₂, S(O)_(t)NR²⁰R²¹, S(O)_(t)R²⁰,C(O)OR²⁰, C(O)R²⁰C(═NR^(a))NR²⁰R²¹, C(═NR²⁰)NR²¹R^(a), C(═NOR²⁰)R²¹ orC(O)NR²⁰R²¹;

each occurrence of R⁷ and R⁸ are each independently: halogen, CF₃, COR⁴,OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴,SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵,(C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall may be optionally substituted;

R⁹ is H or C₁₋₆ alkyl;

R¹⁰ is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵,CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵,NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(CO—C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, B(OH)₂, alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl and aminoalkyl all may be optionally substituted;

R¹¹ and R¹² are each independently: halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂,CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (CO—C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall may be optionally substituted;

R^(13a) and R^(13b) are each independently R⁵ or together are ═O;

R^(14a) and R^(14b) are each independently R⁵ or together are ═O;

R^(13c) and R^(14c) are each independently R⁵;

Q^(a) is CH or N;

U is —C(O)—, —C(═NR⁴)—, —(CR⁴R⁵—)_(p), NR⁵⁰, S(═O)₂, C(═O), (C═O)N(R⁴),N(R⁴)(C═O), S(═O)₂N(R⁴), N(R⁴)S(═O)₂, C═N—OR⁴, —C(R⁴)═C(R⁵)—,—C(R⁴R⁵)_(p)NR⁵⁰—, N(R⁵⁰)C(R⁴R⁵)_(p)—, —O—C(R⁴R⁵)—, —C(R⁴R⁵)S(═O)_(t)—,—(C═O)O—, —(C═NR^(a))N(R⁴)—, —(C═NR^(a))—, N(C═O)NR⁴NR⁵, N(C═O)R⁴,N(C═O)OR⁴, NS(═O)₂NR⁴NR⁵, NS(═O)₂R⁴, or an optionally substituted aryl,heteroaryl, cycloalkyl or heterocyclic ring, all of which may beoptionally substituted;

W is —CH₂—, —S—, —CHF— or —CF₂—;

Z is C or N;

m is 1, or 2;

n is 0, 1, or 2;

p is 0 to 6;

q is 0 to 6; and

t is 0, 1, or 2

wherein: when E and G are both phenyl either:

(1) at least one of R¹ or R² is present and is:

CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵,S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵,(C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(CO—C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, (C₅₋₂₀)alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl and aminoalkyl are all optionally substituted; and whereinOR⁴ is alkoxy, OR⁴ is (C₅₋₂₀) alkoxy; or (2) and when B is (b) R⁷ and R⁸are not selected from hydrogen, hydroxy, hydroxymethyl, and phenyl; or(3) and when B is (b) or (f), R9 is: C₁₋₆ alkyl.

Compounds of the present invention having one or more optically activecarbons can exist as racemates and racemic mixtures, diasteromericmixtures and individual diastereomers, enantiomeric mixtures and singleenantiomers, tautomers, atropisomers, and rotamers, with all isomericforms being included in the present invention. Compounds described inthis invention containing olefinic double bonds include both E and Zgeometric isomers. Also included in this invention are all salt forms,polymorphs, hydrates and solvates. All of the above mentioned compoundsare included within the scope of the invention.

The present invention also provides methods of inhibiting the DPP-IVenzyme.

The present invention further provides methods of treatment orprevention of diseases in which the dipeptidyl peptidase-IV enzyme isinvolved, such as diabetes and particularly Type-2 diabetes.

The present invention also provides methods for obtaining the DPP-IVinhibiting compounds and pharmaceutical compositions comprising themeither singly or in combination with one or more additional therapeuticagents for the prevention or treatment of DPP-IV enzyme medicateddiseases, particularly Type-2 diabetes.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms “alkyl” or “alk”, as used herein alone or as part of anothergroup, denote optionally substituted, straight and branched chainsaturated hydrocarbon groups, preferably having 1 to 10 carbons in thenormal chain, most preferably lower alkyl groups. Exemplaryunsubstituted such groups include methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl,dodecyl and the like. Exemplary substituents may include, but are notlimited to, one or more of the following groups: halo, alkoxy,alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group),cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl(—COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl(NH₂—CO—), substituted carbamoyl ((R⁴)(R⁵)N—CO— wherein R⁴ or R⁵ are asdefined below, except that at least one of R⁴ or R⁵ is not hydrogen),amino, heterocyclo, mono- or dialkylamino, or thiol (—SH).

The terms “lower alk” or “lower alkyl” as used herein, denote suchoptionally substituted groups as described above for alkyl having 1 to 4carbon atoms in the normal chain.

The term “alkoxy” denotes an alkyl group as described above bondedthrough an oxygen linkage (—O—).

The term “alkenyl”, as used herein alone or as part of another group,denotes optionally substituted, straight and branched chain hydrocarbongroups containing at least one carbon to carbon double bond in thechain, and preferably having 2 to 10 carbons in the normal chain.Exemplary unsubstituted such groups include ethenyl, propenyl,isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl,decenyl, and the like. Exemplary substituents may include, but are notlimited to, one or more of the following groups: halo, alkoxy,alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy orprotected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy,alkylcarbonyl, carbamoyl (NH₂—CO—), substituted carbamoyl ((R⁴)(R⁵)N—CO—wherein R⁴ or R⁵ are as defined below, except that at least one of R⁴ orR⁵ is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol(—SH).

The term “alkynyl”, as used herein alone or as part of another group,denotes optionally substituted, straight and branched chain hydrocarbongroups containing at least one carbon to carbon triple bond in thechain, and preferably having 2 to 10 carbons in the normal chain.Exemplary unsubstituted such groups include, but are not limited to,ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, and the like. Exemplary substituents may include, butare not limited to, one or more of the following groups: halo, alkoxy,alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy orprotected hydroxy, carboxyl (—COOH), alkyloxycarbonyl, alkylcarbonyloxy,alkylcarbonyl, carbamoyl (NH₂—CO—), substituted carbamoyl ((R⁴)(R⁵)N—CO—wherein R⁴ or R⁵ are as defined below, except that at least one of R⁴ orR⁵ is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol(—SH).

The term “cycloalkyl”, as used herein alone or as part of another group,denotes optionally substituted, saturated cyclic hydrocarbon ringsystems, including bridged ring systems, desirably containing 1 to 3rings and 3 to 9 carbons per ring. Exemplary unsubstituted such groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, andadamantyl. Exemplary substituents include, but are not limited to, oneor more alkyl groups as described above, or one or more groups describedabove as alkyl substituents.

The terms “ar” or “aryl”, as used herein alone or as part of anothergroup, denote optionally substituted, homocyclic aromatic groups,preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplaryunsubstituted such groups include, but are not limited to, phenyl,biphenyl, and naphthyl. Exemplary substituents include, but are notlimited to, one or more nitro groups, alkyl groups as described above orgroups described above as alkyl substituents.

The term “heterocycle” or “heterocyclic system” denotes a heterocyclyl,heterocyclenyl, or heteroaryl group as described herein, which containscarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O and S and including any bicyclic or tricyclicgroup in which any of the above-defined heterocyclic rings is fused toone or more heterocycle, aryl or cycloalkyl groups. The nitrogen andsulfur heteroatoms may optionally be oxidized. The heterocyclic ring maybe attached to its pendant group at any heteroatom or carbon atom whichresults in a stable structure. The heterocyclic rings described hereinmay be substituted on carbon or on a nitrogen atom.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolinyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl,oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,oxindolyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl,1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl,thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl.

“Heterocyclenyl” denotes a non-aromatic monocyclic or multicyclichydrocarbon ring system of about 3 to about 10 atoms, desirably about 4to about 8 atoms, in which one or more of the carbon atoms in the ringsystem is/are hetero element(s) other than carbon, for example nitrogen,oxygen or sulfur atoms, and which contains at least one carbon-carbondouble bond or carbon-nitrogen double bond. Ring sizes of rings of thering system may include 5 to 6 ring atoms. The designation of the aza,oxa or thia as a prefix before heterocyclenyl define that at least anitrogen, oxygen or sulfur atom is present respectively as a ring atom.The heterocyclenyl may be optionally substituted by one or moresubstituents as defined herein. The nitrogen or sulpHur atom of theheterocyclenyl may also be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. “Heterocyclenyl” as used hereinincludes by way of example and not limitation those described inPaquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A.Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9;“The Chemistry of Heterocyclic Compounds, A series of Monographs” (JohnWiley & Sons, New York, 1950 to present), in particular Volumes 13, 14,16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960), the contentsall of which are incorporated by reference herein. Exemplary monocyclicazaheterocyclenyl groups include, but are not limited to,1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl,1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl,3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Exemplaryoxaheterocyclenyl groups include, but are not limited to,3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl. Anexemplary multicyclic oxaheterocyclenyl group is7-oxabicyclo[2.2.1]heptenyl.

“Heterocyclyl,” or “heterocycloalkyl,” denotes a non-aromatic saturatedmonocyclic or multicyclic ring system of about 3 to about 10 carbonatoms, desirably 4 to 8 carbon atoms, in which one or more of the carbonatoms in the ring system is/are hetero element(s) other than carbon, forexample nitrogen, oxygen or sulfur. Ring sizes of rings of the ringsystem may include 5 to 6 ring atoms. The designation of the aza, oxa orthia as a prefix before heterocyclyl define that at least a nitrogen,oxygen or sulfur atom is present respectively as a ring atom. Theheterocyclyl may be optionally substituted by one or more substituentswhich may be the same or different, and are as defined herein. Thenitrogen or sulpHur atom of the heterocyclyl may also be optionallyoxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.

“Heterocyclyl” as used herein includes by way of example and notlimitation those described in Paquette, Leo A.; “Principles of ModernHeterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularlyChapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds,A series of Monographs” (John Wiley & Sons, New York, 1950 to present),in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”,82:5566 (1960). Exemplary monocyclic heterocyclyl rings include, but arenot limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Heteroaryl” denotes an aromatic monocyclic or multicyclic ring systemof about 5 to about 10 atoms, in which one or more of the atoms in thering system is/are hetero element(s) other than carbon, for examplenitrogen, oxygen or sulfur. Ring sizes of rings of the ring systeminclude 5 to 6 ring atoms. The “heteroaryl” may also be substituted byone or more substituents which may be the same or different, and are asdefined herein. The designation of the aza, oxa or thia as a prefixbefore heteroaryl define that at least a nitrogen, oxygen or sulfur atomis present respectively as a ring atom. A nitrogen atom of a heteroarylmay be optionally oxidized to the corresponding N-oxide. Heteroaryl asused herein includes by way of example and not limitation thosedescribed in Paquette, Leo A.; “Principles of Modern HeterocyclicChemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3,4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series ofMonographs” (John Wiley & Sons, New York, 1950 to present), inparticular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”,82:5566 (1960). Exemplary heteroaryl and substituted heteroaryl groupsinclude, but are not limited to, pyrazinyl, thienyl, isothiazolyl,oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl,pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine,imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl,benzothienyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl,imidazopyridyl, benzoazaindole, 1,2,3-triazinyl, 1,2,4-triazinyl,1,3,5-triazinyl, benzthiazolyl, dioxolyl, furanyl, imidazolyl, indolyl,indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, morpholino,oxadiazolyl, oxazinyl, oxiranyl, piperazinyl, piperidinyl, pyranyl,pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl,pyrrolidinyl, quinazolinyl, quinolinyl, tetrazinyl, tetrazolyl,1,3,4-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, thiatriazolyl, thiazinyl, thiazolyl, thienyl,5-thioxo-1,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl,triazolyl and triazolonyl.

The term “amino” denotes the radical —NH₂ wherein one or both of thehydrogen atoms may be replaced by an optionally substituted hydrocarbongroup. Exemplary amino groups include, but are not limited to,n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.

The term “cycloalkylalkyl” denotes a cycloalkyl-alkyl group wherein acycloalkyl as described above is bonded through an alkyl, as definedabove. Cycloalkylalkyl groups may contain a lower alkyl moiety.Exemplary cycloalkylalkyl groups include, but are not limited to,cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl,cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl,cyclopentylpropyl, and cyclohexylpropyl.

The term “arylalkyl” denotes an aryl group as described above bondedthrough an alkyl, as defined above.

The term “heteroarylalkyl” denotes a heteroaryl group as described abovebonded through an alkyl, as defined above.

The term “heterocyclylalkyl,” or “heterocycloalkylalkyl,” denotes aheterocyclyl group as described above bonded through an alkyl, asdefined above.

The terms “halogen”, “halo”, or “hal”, as used herein alone or as partof another group, denote chlorine, bromine, fluorine, and iodine.

The term “haloalkyl” denotes a halo group as described above bondedthough an alkyl, as defined above. Fluoroalkyl is an exemplary group.

The term “aminoalkyl” denotes an amino group as defined above bondedthrough an alkyl, as defined above.

The pHrase “bicyclic fused ring system wherein at least one ring ispartially saturated” denotes an 8- to 13-membered fused bicyclic ringgroup in which at least one of the rings is non-aromatic. The ring grouphas carbon atoms and optionally 1-4 heteroatoms independently selectedfrom N, O and S. Illustrative examples include, but are not limited to,indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.

The pHrase “tricyclic fused ring system wherein at least one ring ispartially saturated” denotes a 9- to 18-membered fused tricyclic ringgroup in which at least one of the rings is non-aromatic. The ring grouphas carbon atoms and optionally 1-7 heteroatoms independently selectedfrom N, O and S. Illustrative examples include, but are not limited to,fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.

The term “pharmaceutically acceptable salts” refers to derivatives ofthe disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as, but not limited to, hydrochloric, hydrobromic, sulfuric,sulfamic, phosphoric, nitric and the like; and the salts prepared fromorganic acids such as, but not limited to, acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two. Organic solventsinclude, but are not limited to, nonaqueous media like ethers, ethylacetate, ethanol, isopropanol, or acetonitrile. Lists of suitable saltsare found in Remington's Pharmaceutical Sciences, 18th ed., MackPublishing Company, Easton, Pa., 1990, p. 1445, the disclosure of whichis hereby incorporated by reference.

The pHrase “pharmaceutically acceptable” denotes those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problem or complication commensurate with areasonable benefit/risk ratio.

“Substituted” is intended to indicate that one or more hydrogens on theatom indicated in the expression using “substituted” is replaced with aselection from the indicated group(s), provided that the indicatedatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substituent is keto (i.e., ═O) group, then2 hydrogens on the atom are replaced.

Unless moieties of a compound of the present invention are defined asbeing unsubstituted, the moieties of the compound may be substituted. Inaddition to any substituents provided above, the moieties of thecompounds of the present invention may be optionally substituted withone or more groups independently selected from, but not limited to:

C₁-C₄ alkyl;

C₂-C₄ alkenyl;

C₂-C₄ alkynyl;

CF₃;

halo;

OH;

O—(C₁-C₄ alkyl);

OCH₂F;

OCHF₂;

OCF₃;

COCF₃;

OC(O)—(C₁-C₄ alkyl);

OC(O)NH—(C₁-C₄ alkyl);

OC(O)N(C₁-C₄ alkyl)₂;

OC(S)NH—(C₁-C₄ alkyl);

OC(S)N(C₁-C₄ alkyl)₂;

ONO₂;

SH;

S—(C₁-C₄ alkyl);

S(O)—(C₁-C₄ alkyl);

S(O)₂—(C₁-C₄ alkyl);

SC(O)—(C₁-C₄ alkyl);

SC(O)O—(C₁-C₄ alkyl);

NH₂;

N(H)—(C₁-C₄ alkyl);

N(C₁-C₄ alkyl)₂;

N(H)C(O)—(C₁-C₄ alkyl);

N(CH₃)C(O)—(C₁-C₄ alkyl);

N(H)C(O)—CF₃;

N(CH₃)C(O)—CF₃;

N(H)C(S)—(C₁-C₄ alkyl);

N(CH₃)C(S)—(C₁-C₄ alkyl);

N(H)S(O)₂—(C₁-C₄ alkyl);

N(H)C(O)NH₂;

N(H)C(O)NH—(C₁-C₄ alkyl);

N(CH₃)C(O)NH—(C₁-C₄ alkyl);

N(H)C(O)N(C₁-C₄ alkyl)₂;

N(CH₃)C(O)N(C₁-C₄ alkyl)₂;

N(H)S(O)₂NH₂);

N(H)S(O)₂NH—(C₁-C₄ alkyl);

N(CH₃)S(O)₂NH—(C₁-C₄ alkyl);

N(H)S(O)₂N(C₁-C₄ alkyl)₂;

N(CH₃)S(O)₂N(C₁-C₄ alkyl)₂;

N(H)C(O)O—(C₁-C₄ alkyl);

N(CH₃)C(O)O—(C₁-C₄ alkyl);

N(H)S(O)₂O—(C₁-C₄ alkyl);

N(CH₃)S(O)₂O—(C₁-C₄ alkyl);

N(CH₃)C(S)NH—(C₁-C₄ alkyl);

N(CH₃)C(S)N(C₁-C₄ alkyl)₂;

N(CH₃)C(S)O—(C₁-C₄ alkyl);

N(H)C(S)NH₂;

NO₂;

CO₂H;

CO₂—(C₁-C₄ alkyl);

C(O)N(H)OH;

C(O)N(CH₃)OH:

C(O)N(CH₃)OH;

C(O)N(CH₃)O—(C₁-C₄ alkyl);

C(O)N(H)—(C₁-C₄ alkyl);

C(O)N(C₁-C₄ alkyl)₂;

C(S)N(H)—(C₁-C₄ alkyl);

C(S)N(C₁-C₄ alkyl)₂;

C(NH)N(H)—(C₁-C₄ alkyl);

C(NH)N(C₁-C₄ alkyl)₂;

C(NCH₃)N(H)—(C₁-C₄ alkyl);

C(NCH₃)N(C₁-C₄ alkyl)₂;

C(O)—(C₁-C₄ alkyl);

C(NH)—(C₁-C₄ alkyl);

C(NCH₃)—(C₁-C₄ alkyl);

C(NOH)—(C₁-C₄ alkyl);

C(NOCH₃)—(C₁-C₄ alkyl);

CN;

CHO;

CH₂OH;

CH₂O—(C₁-C₄ alkyl);

CH₂NH₂;

CH₂N(H)—(C₁-C₄ alkyl);

CH₂N(C₁-C₄ alkyl)₂;

aryl;

heteroaryl;

cycloalkyl; and

heterocyclyl.

The term “cleave” or “cleaving” means splitting a complex molecule intoat least two separate molecules. “Cleavage products” are the separatemolecules which result from cleaving.

The term “metabolite” refers to a composition which results from ametabolic process. Examples of the results of metabolism on thecompounds of the present invention include addition of —OH, hydrolysis,and cleavage.

The term “polymorphs” refers to the various crystalline structures ofthe compounds of the present invention. This may include, but is notlimited to, crystal morphologies (and amorphous materials), all crystallattice forms, and all salts. Salts of the present invention can becrystalline and may exist as more than one polymorpH. Each polymorpHforms another aspect of the invention. Hydrates as well as anhydrousforms of the salt are also encompassed by the invention.

“Teoc” is 2-(trimethylsilyl)ethoxycarbonyl

“Et” is ethyl (—CH₂CH₃) or ethylene (—CH₂CH₂—).

“Me” is methyl (—CH₃) or methylene (—CH₂—).

“Boc” is tert-butyloxycarbonyl.

“PHCH₂” is benzyl.

The term “pharmaceutically-acceptable tricyclic moiety” is meant toinclude, but is not limited to, benzocycloheptapyridyl, benzodiazepinyl,and benzozapinyl

In another embodiment of the present invention, the DPP-IV inhibitingcompounds are used in the manufacture of a medicament for the treatmentof a disease mediated by an DPP-IV enzyme.

In another aspect, the DPP-IV inhibiting compounds of the presentinvention are used in combination with another disease modifying drug.Examples of other disease modifying drugs include, but are not limitedto: (a) other dipeptidyl peptidase IV (DPP-IV) inhibitors such asVildagliptin (Novartis), Sitagliptin (Merck&Co.), Saxagliptin (BMS); (b)insulin sensitizers including (i) PPARγ agonists such as the glitazones(e.g. troglitazone, pioglitazone, edaglitazone, rosiglitazone, and thelike) and other PPAR ligands, including PPARα/γ dual agonists such asmuraglitazar (BMS) and tesaglitazar (AstraZeneca), and PPARα agonistssuch as fenofibric acid derivatives (gemfibrozil, clofibrate,fenofibrate and bezafibrate), (ii) biguanides such as metformin andphenformin, and (iii) protein tyrosine phosphatase-1B (PTP-1B)inhibitors; (c) insulin or insulin mimetics; (d) incretin and incretinmimetics such as (i) Exenatide available from Amylin Pharmaceuticals,(i) amylin and amylin mimetics such as pramlintide acetate, available asSymlin®, (iii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists, (iv)GIP, GIP mimetics and GIP receptor agonists; (e) sulfonylureas and otherinsulin secretagogues, such as tolbutamide, glyburide, glipizide,glimepiride, meglitinides, and repaglinide; (f) α-glucosidase inhibitors(such as acarbose and miglitol); (g) glucagon receptor antagonists; (h)PACAP, PACAP mimetics, and PACAP receptor agonists; (i) cholesterollowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin,simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin,itavastatin, and rosuvastatin, and other statins), (ii) sequestrantssuch as cholestyramine, colestipol and dialkylaminoalkyl derivatives ofa cross-linked dextran, (iii) nicotinyl alcohol, nicotinic acid or asalt thereof, (iv) PPARα agonists such as fenofibric acid derivatives(gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v) PPARα/γ dualagonists such as muraglitazar (BMS) and tesaglitazar (AstraZeneca), (vi)inhibitors of cholesterol absorption, such as beta-sitosterol andezetimibe, (vii) acyl CoA:cholesterol acyltransferase inhibitors such asavasimibe, and (viii) anti-oxidants such as probucol; (J) PPARδ agonistssuch as GW-501516 from GSK; (k) anti-obesity compounds such asfenfluramine, dexfenfluramine, phentemine, sibutramine, orlistat,neuropeptide Y1 or Y5 antagonists, MTP inhibitors, squalene synthaseinhibitor, lipoxygenase inhibitor, ACAT inhibitor, NeuropeptideCannabinoid CB-1 receptor antagonists, CB-1 receptor inverse agonistsand antagonists, fatty acid oxidation inhibitors, appetite suppressants(1) adrenergic receptor agonists, melanocortin receptor agonists, inparticular—melanocortin-4 receptor agonists, ghrelin antagonists, andmelanin-concentrating hormone (MCH) receptor antagonists; (m) ileal bileacid transporter inhibitors; (n) agents intended for use in inflammatoryconditions such as aspirin, non steroidal anti-inflammatory drugs,glucocorticoids, azalfidine, and selective cyclooxygenase-2 inhibitors;(o) antihypertensive agents such as ACE inhibitors (enalapril,lisinopril, captopril, quinapril, fosinoprol, ramipril, spirapril,tandolapril), angiotensin-II (AT-1) receptor blockers (losartan,candesartan, irbesartan, valsartan, telmisartan, eprosartan), betablockers and calcium channel blockers; and (p) glucokinase activators(GKAs); (q) agents which can be used for the prevention, delay ofprogression or treatment of neurodegenerative disorders, cognitivedisorders or a drug for improving memory such as anti-inflammatorydrugs, antioxidants, neuroprotective agents, glutamate receptorantagonists, acetylcholine esterase inhibitors, butyrylcholinesteraseinhibitors, MAO inhibitors, dopamine agonists or antagonists, inhibitorsof gamma and beta secretases, inhibitors of amyloid aggregation, amyloidbeta peptide, antibodies to amyloid beta peptide, inhibitors ofacetylcholinesterase, glucokinase activators, agents directed atmodulating GABA, NMDA, cannabinoid, AMPA, kainate, phosphodiesterase(PDE), PKA, PKC, CREB or nootropic systems; (r) leukocyte growthpromotors intended for the treatment and prevention of reduced bonemarrow production, infectious diseases, hormone dependent disorders,inflammatory diseases, HIV, allergies, leukocytopenia, and rheumatism;(s) SGLT2 inhibitor; (t) glycogen phosphorylase inhibitor; (u) aP2inhibitors; (v) aminopeptidase N inhibitor (w) vasopeptidase inhibitorslike neprilysin inhibitors and/or ACE inhibitors or dual NEP/ACEinhibitor; (x) growth hormone secretagogue for enhancing growth hormonelevels and for treating growth retardation/dwarfism or metabolicdisorders or where the disorder is an injury, or a wound in need ofhealing, or a mammalian patient recovering from surgery; (y) 5-HT 3 or5-HT 4 receptor modulators (tegaserod, cisapride, nor-cisapride,renzapride, zacopride, mosapride, prucalopride, buspirone, norcisapride,cilansetron, ramosetron, azasetron, ondansetron, etc.); (Za) aldosereductase inhibitors; (Zb) sorbitol dehydrogenase inhibitors; (Zc) AGEinhibitors; (Zd) erythropoietin agonist such as EPO, EPO mimetics, andEPO receptor agonists.

In a further aspect, the DPP-IV inhibiting compounds of the presentinvention are used in the treatment diseases or symptoms mediated by anDPP-IV enzyme. Examples of diseases or symptoms mediated by a DPP-IVenzyme include, but are not limited to, Type II (Type-2) Diabetes andRelated Disorders, such as hyperglycemia, low glucose tolerance, insulinresistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDLlevels, atherosclerosis and its 30 sequelae, vascular restenosis,irritable bowel syndrome, inflammatory bowel disease, including Crohn'sdisease and ulcerative colitis, other inflammatory conditions,pancreatitis, abdominal obesity, neurodegenerative disease, retinopathy,nepHropathy, neuropathy, cataracts, glaucoma, glomerulosclerosis, footulcerations and unlcerative colitis, altered gastrointestinal motility,Syndrome X, ovarian hyperandrogenism, polycystic ovarian syndrome,premenstrual syndrome, other disorders where insulin resistance is acomponent. In Syndrome X, also known as Metabolic Syndrome, obesity isthought to promote insulin resistance, diabetes, dyslipidemia,hypertension, and increased cardiovascular risk, growth hormonedeficiency, neutropenia, neuronal disorders, tumor invasion andmetastasis, benign prostatic hypertrophy, gingivitis, osteoporosis,frailty of aging, intestinal injury, benign prostatic hypertrophy (BPH),and sperm motility/male contraception.

In a further aspect, the DPP-IV inhibiting compounds of the presentinvention are useful for the prevention, delay of progression or thetreatment of an early cardiac or early cardiovascular diseases ordamages, renal diseases or damages, heart Failure, or heart Failureassociated diseases like (i) cardiovascular diseases or damages e.g.cardiac hypertrophy, cardiac remodelling after myocardial infarction,pulmonary congestion and cardiac fibrosis in dilated or in hypertrophiccardiomyopathy, cardiomyopathy such as dilated cardiomyopathy orhypertrophic cardiomyopathy, mesanglial hypertrophy, or diabeticcardiomyopathy, left or right ventricular hypertrophy, arrhythmia,cardiac dysrhythmia, syncopy, angina pectoris, cardiac bypassreocclusion, intermittent claudication, diastolic and/or systolicdysfunction, diabetic myopathy, stroke prevention in congestive heartfailure, hypertrophic medial thickening in arteries and/or largevessels, mesenteric vasculature hypertrophy or artherosclerosis,preferably artherosclerosis in mammalian patients with hypertension ofdiabetes; (ii) renal diseases or damages like renal hyperfiltration suchas after portal renal ablation, proteinuria in chronic renal disease,renal arteriopathy as a consequence of hypertension, nepHrosclerosis,hypertensive nepHrosclerosis or mesanglial hypertrophy; (iii) HeartFailure to be treated is secondary to idiopathic dilated cardiomyopathyand/or coronary ischemic disease;

In another aspect, the DPP-IV inhibiting compounds of the presentinvention are used for the prevention, the delay of the onset, the delayof progression or the treatment of neurodegenerative disorders,cognitive disorders and for improving memory (both short term and longterm) and learning ability wherein the (i) neurodegenerative disorder isdementia, senile dementia, schizopHrenia, mild cognitive impairment,Alzheimer related dementia, Huntington's chores, tardive dyskinesia,hyperkinesias, mania, Morbus Parkinson, Steel-Richard syndrome, Down'ssyndrome, myasthenia gravis, nerve and brain trauma, vascularamyloidosis, cerebral haemorrhage I with amyloidosis, braininflammation, Friedrich ataxia, acute confusion disorders, acuteconfusion disorders with apoptotic necrocytosis, amyotrophic lateralsclerosis, glaucoma, and Alzheimer's disease; (ii) cognitive disorderslike cognitive deficits associated with schizopHrenia, age-inducedmemory impairment, cognitive deficits associated with psychosis,cognitive impairment associated with diabetes, cognitive deficitsassociated with post-stroke, memory defects associated hypoxia,cognitive and attention deficits associated with senile dementia,attention deficits disorders, memory problems associated with mildcognitive impairment, impaired cognitice function associated withvascular dementia, cognitive problems associated with brain tumors,Pick's disease, cognitive deficits due to autism, cognitive deficitspost electroconvulsive therapy, cognitive deficits associated withtraumatic brain injury, amnesic disorders, deliriums, vitamindeficiency, dementias, impaired cognitive function associated withParkinson's disease, attention-deficit disorders; (iii) prevention ofmemory impairment as a result of Alzheimer disease, Creutzfeld-Jakobdisease, Pick disease, Huntington disease, AIDS, brain injury, brainaneurysm, epilepsy, stroke, toxicant exposure, mental retardation inchildren, Huntington's disease; (iv) to improve learning speed andpotential in educational and rehabilitation contexts.

In another aspect, the DPP-IV inhibiting compounds of the presentinvention are used for stimulating an immune response in a subjecthaving or at risk of having cancer wherein the cancer is selected fromthe group consisting of basal cell carcinomas including cancers of thebinary tract, bladder, urinary system, bone, brain, breast, cervical,endometrial, ovarian, uterine, choriocarcinoma, central nervous system,colon and rectal cancers, connective tissue cancer, cancer of thedigestive system, esophageal, gastric, stomach, larynx, liver,pancreatic, colorectal, renal cancers; cancers of the urinary system;cancers of eye, head and neck, oral cavity, skin, prostate; cancers ofbiliary tract, testicular, thyroid; intra-epithelial neoplasm, leukemia,acute myeloid leukemia, acute lymphoid leukemia, chronic myeloidleukemia, chronic lymphoid leukemia; and other cancers of therespiratory system, lung, small cell lung, non-small cell lung;lymphoma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma; melanoma, myeloma,neuroblastoma, retinoblastoma, fibrosarcoma (bone or connective tissuesarcoma), rhabdomyosarcoma; and other cancers including neoplasticconditions, adipose cell tumors, adipose cell carcinomas, such asliposarcoma;

In a further aspect, the DPP-IV inhibiting compounds of the presentinvention are useful for the treatment or prophylaxis of chronicinflammatory diseases such as autoimmune disorders like rheumatoidarthritis, systemic lupus erythematosus, multiple sclerosis, psoriasis,allergies or asthma.

In another aspect, the DPP-IV inhibiting compounds of the presentinvention may be useful in the treatment of pain, neuropathic pain,rheumatoid pain, osteoarthritis pain, anesthesia adjunct in mammalianpatients undergoing surgery, chronic pain in advanced cancer, treatmentof refractory diarrhea, biliary pain caused by gallstones.

In a further aspect, the DPP-IV inhibiting compounds of the presentinvention are useful for the treatment of mammalian patients undergoingislet/pancreas transplantation, for the prevention or the delay oftransplant rejection, or allograft rejection in transplantation, forimproving pancreatic function by increasing the number and size ofpancreatic beta-cells in the treatment of Type 1 diabetes patients, andfor improving pancreatic function by increasing the number and size ofpancreatic beta-cells in general.

Furthermore, the DPP-IV inhibiting compounds of the present inventionare useful for the treatment of mammalian patients with acne, skindisorders (e.g. pigmentation disorders or psoriasis), scleroderma,mycoses; anxiety, anxiety neurosis, major depression disorder, drugabuse, alcohol addiction, insomnia, chronic fatigue, sleep apnea;anorexia nervosa; epilepsy; migrane; encephalomyelitis; osteoarthritis,osteoporosis, calcitonin-induced osteoporosis; male and female sexualdysfunction, infertility; Type 1 diabetes; immunosuppression, HIVinfection; hematopoiesis, anemia; and for weight reduction.

In a further aspect, the DPP-IV inhibiting compounds of the presentinvention are useful for the prevention, delay of progression ortreatment of (i) bacterial infections from Escherichia coli,Staphylococcus, Streptoococcus, Pseudomonas, Clostridium difficileinfection, Legionella, Pneumococcus, HaemopHilus, Klebsiella,Enterobacter, Citrobacter, Neisseria, Shigella, Salmonella, Listeria,Pasteurella, Streptobacillus, Spirillum, Treponema, Actinomyces,Borrelia, Corynebacterium, Nocardia, Gardnerella, Campylobacter,Spirochaeta, Proteus, Bacteriodes, Helicobacter pylori, and anthraxinfection; (ii) mycobacterial infection from tuberculosis and leprosy;(iii) viral infection from HIV, Herpes simplex virus 1, Herpes simplexvirus 2, Cytomegalovirus, hepatitis A virus, hepatitis B virus,hepatitis C virus, human papilloma virus, Epstein Barr virus, rotavirus,adenovirus, influenza A virus, respiratory syncytial virus,varicella-zoster virus, small pox, monkey pox and SARS; (iv) fungalinfection from candidiasis, ringworm, histoplasmosis, blastomycosis,paracoccidioidomycosis, cryptococcosis, aspergillosis, chromomycosis,mycetoma infections, pseudallescheriasis, Tinea versicolor infection;(v) parasite infection from amebiasis, Trypanosoma cruzi, Fascioliasis,Leishmaniasis, Plasmodium, Onchocerciasis, Paragonimiasis, Trypanosomabrucei, Pneumocystis, Trichomonas vaginalis, Taenia, Hymenolepsis,Echinococcus, Schistosomiasis, neurocysticerosis, Necator americanus,and Trichuris trichuria.

The compounds from this invention are suitable for oral, sublingual,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (aerosol inhalation), ornasal administration, although the most suitable route in any given casewill depend on the nature and severity of the conditions being treatedand on the nature of the active ingredient. The compounds from thisinvention are conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

The DPP-IV inhibiting compounds of the present invention are synthesizedby the general method shown in Schemes 1-14.

Generic Schemes

General synthetic schemes for the preparation of tricyclic buildingblocks of this invention:

Commercially available bromotoluene derivatives were treated withn-butyllithium and heated, followed by treatment with dry-ice in anappropriate solvent to afford the desired compound. Alternatively, theacid can be prepared by Grignard reaction followed by treatment withdry-ice in an appropriate solvent. Esterification of the compoundfollowed by NBS bromination and subsequent conversion to the phosphoniumsalt in a suitable solvent and heating affords the desired compound.Wittig reaction of the phosphonium salt with a suitable aldehyde in anappropriate solvent and heating, followed by saponification of the estermoiety and subsequent catalytic hydrogenation affords the desiredcompound. Cyclisation of the compound with polyphosphoric acid insulfolane and heating affords the desired compound after purification.For R₁═COOMe the tricyclic product from the polyphosphoric acid step wastreated with thionylchloride in an alcohol. Reduction of the ketone witha metal hydride in an appropriate solvent yields the compound afterpurification. Treatment of the alcohol with thionylchloride in asuitable solvent affords the final desired compound. In order to obtainthe compounds with R₁═R₂═COOMe, the tricyclic product from thepolyphosphoric acid step with R₁═COOH and R₂=Br was treated with CuCN ina suitable solvent, followed by saponification of the nitrile to theacid. Ester formation using thionylchloride in an alcohol and reductionof the ketone with a metal hydride in an appropriate solvent yields thecompound after purification. Treatment of the alcohol withthionylchloride in a suitable solvent affords the final desiredcompound.

Alternative synthetic scheme for the preparation of tricyclic buildingblocks of this invention:

Commercially available bromotoluene derivatives are treated withMagnesium in a Grignard reaction followed by treatment with dry-ice inan appropriate solvent to yield the desired acid. This acid is thentreated with sec-butyllithium in an appropriate solvent at lowertemperature. The anion is added at lower temperature to a solution of acommercially available benzylchloride in an appropriate solvent toafford the desired compound. Cyclisation of the compound withpolyphosphoric acid in sulfolane and heating affords the desiredcompound. To obtain the compounds with R₁═R₂═COOMe, the tricyclicproduct from the polyphosphoric acid step with R₁═R₂═Cl was treated withKCN, a Pd-catalyst, a suitable ligand and a suitable base in anappropriate solvent to afford the dicyano compound, which was convertedto the diacid by treatment with base in a suitable solvent. Esterformation using thionylchloride in an alcohol and reduction of theketone with a metal hydride in an appropriate solvent yields thecompound after purification. Treatment of the alcohol withthionylchloride in a suitable solvent affords the final desiredcompound.

General synthetic scheme for the preparation of aldehyde building blocksof this invention:

Commercially available prolinamide is treated with fumarylchloride in anappropriate solvent to afford the desired compound. This compound isthen treated with oxalylchloride in dimethylformamide to afford thedesired compound after purification. Alternatively, the coupling productof prolinamide with fumarylchloride can be treated with trifluoroaceticacid anhydride in a suitable solvent to afford the desired compound.Ozonolysis of this compound at −78° C. in a suitable solvent, followedby reductive workup affords the desired final compound as a mixture ofthe aldehyde and its methyl hemiacetal.

Treatment of 2-Aza-bicyclo[3.1.0]hexane-3-carboxylic acid amide,prepared according to WO 01/68603, in the same manner as described aboveyields the desired final compound containing a cyclopropyl moiety at the4,5-position of the pyrrolidine moiety.

General synthetic scheme for the preparation of tricyclic compounds ofthis invention with R³═H:

The reaction of substituted or unsubstituted tricyclic chlorides with anamino derivative in a suitable solvent as described above affords thedesired final product after purification. Substituted or unsubstitutedtricyclic chlorides are treated in an appropriate solvent with an excessof suitable amines to afford the desired product after purification. Incase the reaction product contains additional amino protecting groupslike Boc, they are cleaved by acid treatment to afford the desiredcompound. Using these amines for a nucleopHilic displacement reaction ina suitable solvent with a suitable bromo derivative yields the finaldesired product after purification. Alternatively, the amines aretreated with a suitable aldehyde (D-CHO) via reductive amination toafford the final compound after purification.

General synthetic scheme for the preparation of tricyclic compounds ofthis invention with Z=N:

Substituted or unsubstituted tricycles containing a nitrogen at thedoubly benzylic position are treated with bromoacetylbromide and heatedto afford the desired compounds. Treating these compounds with sodiumazide or sodium cyanide in a suitable solvent and heating affords thedesired azido or cyano compounds after purification. Catalytichydrogenation or reduction with Lithium aluminium hydride in a suitablesolvent affords the desired amine compounds. Using these amines for anucleopHilic displacement reaction in a suitable solvent with a suitablebromo derivative yields the final desired product after purification.

General synthetic scheme for the preparation of tricyclic compounds ofthis invention having H, OH or no substituent at R³

Substituted or unsubstituted tricyclic ketones with Y═C(R₄)═C(R₅) aretreated with malonic acid at elevated temperatures to afford the desiredproduct after purification. These compounds are converted to thecorresponding amides by treatment with isobutylchloroformate andammonia. The amides are then converted to the desired amine productswith Y═C(R₄)═C(R₅) by reduction with lithium aluminium hydride or to thedesired amine products with Y═C(R₄R₅)C(R₄R₅) by reduction with lithiumaluminium hydride followed by catalytic hydrogenation with a suitablecatalyst. Using these amines for a nucleopHilic displacement reaction ina suitable solvent with a suitable bromo derivative described aboveyields the final desired product after purification.

Treating tricyclic ketones in a Reformatskij reaction affords thedesired product after purification. Reduction with LiAlH₄ in a suitablesolvent affords the alcohol products with R₃═OH after purification.Activation of one of the hydroxyl groups with sulfonylchlorides in asuitable solvent followed by treatment with NaN₃ affords the desiredcompounds after purification. Reduction of the azide reaction productswith a catalyst in a suitable solvent affords the desired aminecompounds after purification. Using these amines for a nucleopHilicdisplacement reaction in a suitable solvent with a suitable bromoderivative described above yields the final desired products afterpurification.

Treating the amines with R₃═OH with acid in a suitable solvent yieldsthe desired unsaturated amine products. Using these amines for anucleopHilic displacement reaction in a suitable solvent with a suitablebromo derivative described above yields the final desired products afterpurification.

General synthetic schemes (7-9) for the preparation of tricycliccompounds of this invention with R³=nitrile, amide, tetrazolyl orN-alkyl-tetrazolyl

Substituted or unsubstituted suberylchlorides are treated in a suitablesolvent with a slight excess of AgCN and heated to afford the desiredproduct after purification. The nitrile containing compound is thentreated with sodium hydride in a suitable solvent and heated. Themixture is then treated at rt with a suitable dibromoalkene and heatedto give an intermediate which after treatment with sodium azide orpotassium phthalimide in an appropriate solvent and heating affords thedesired compound after purification. Treating the mixture after theaddition of sodium hydride at rt with a suitable sulfamidate in anappropriate solvent affords the desired Teoc-protected compound afterheating for several hours and subsequent purification.

Catalytic hydrogenation of compounds with R′═N₃ in a suitable solventand in the presence of a slight excess of acid affords the free aminecompounds. Coupling of these amines with a suitable aldehyde (CHO-D) viareductive amination and subsequent purification affords the finaldesired compounds with R³═CN.

Catalytic hydrogenation of compounds with R₃═CN and R′═N₃ in a suitablesolvent and in the presence of a slight excess of acid affords the freeamine compounds. Treatment of the hydrogenation products with sulphuricacid affords the desired compounds after purification. In caseR₁═R₂≠COOH, the amines are reacted with a suitable aldehyde (D-CHO) inan appropriate solvent to yield the desired final compounds withR₃═CONH₂ and R₁═R₂≠COOH, CONR₄R₅, COOMe. In case R₁═COOH, the amines aretreated with Boc₂O in a suitable solvent to afford the Boc-protectedamines. These compounds are then treated with ethylchloroformate,followed by treatment with an amine to yield the desired compounds afterpurification. The compounds are then treated with acid, followed byreaction with a suitable aldehyde (D-CHO) in an appropriate solvent toyield the desired final compounds with R₃═CONH₂ and R₁═CONR₄R₅ afterpurification.

The compounds with R₃═CN and R′═N-phthaloyl are treated with an excessof trimethylsilyl azide and Bu₂SnO in an appropriate solvent and heatingto afford the desired compounds with R₃=tetrazolyl and R′═N-phthaloyl.In case R₁═R₂≠COOH, the compounds are treated with hydrazine hydrate atelevated temperature in an appropriate solvent to yield the desiredamines with R₃=tetrazoyl. The reaction of these amines with a suitablealdehyde (D-CHO) in an appropriate solvent affords the desired finalcompound with R₃=tetrazoyl and R₁═R₂≠COOH, CONR₄R₅, COOMe afterpurification. In case R₁═COOMe, the compounds are treated with anappropriate amine in a suitable solvent to afford the free aminecompounds. Protection of the amines with Boc₂O affords the Boc-protectedproducts after purification. Saponification of the ester moietiesaffords the desired fNH-Boc-protected carboxylic acid derivatives. Theacid derivates are then treated with ethylchloroformate, followed by anamine to afford the desired products after acid treatment. The reactionof these amines with a suitable aldehyde (D-CHO) in an appropriatesolvent affords the desired final compound with R₃=tetrazoyl andR₁═CONR₄R₅ after purification.

The NH Teoc-protected compounds with R₃═CN and R₁═R₂═COOMe or R₁═R₂=Halwere treated with hydroxylamine hydrochloride and an excess of base atelevated temperatures in an appropriate solvent to afford the desiredcompounds with R₃═CONH₂ after purification. The same NH Teoc protectedcompounds are also reacted with sodium azide and ammonium chloride in asuitable solvent to yield the desired compounds with R₃=tetrazoyl afterpurification. Further reaction of the compound with R₃=tetrazoyl withmethyl iodide and base in a suitable solvent leads to the formation ofthe desired compound with R₃═N-Me-tetrazoyl after purification. For thecompounds with R₃=tetrazoyl, N-Me-tetrazoyl and R₁═R₂═COOMe, Hal, theTeoc protecting group is removed by treatment with acid to afford thedesired amine compounds. The reaction of these amines with a suitablealdehyde (D-CHO) in an appropriate solvent affords the desired finalcompound with R₃=tetrazoyl, N-Me-tetrazoyl and R₁═R₂═COOMe, Hal afterpurification. For the compounds with R₃=tetrazoyl, N-Me-tetrazoyl andR₁═R₂═COOMe, the ester moieties are removed by treatment with base in anappropriate solvent to afford the desired dicarboxylic acid derivativesafter purification. Treatment of these compounds withethylchloroformate, followed by an amine yields the desired aminecompounds with R₃=tetrazoyl, N-Me-tetrazoyl and R₁═R₂═CONR4R5 afterpurification. Cleavage of the Teoc protecting group with acid affordsthe corresponding amine compounds. The reaction of these amines with asuitable aldehyde (D-CHO) in an appropriate solvent affords the desiredfinal compounds with R₃=tetrazoyl, N-Me-tetrazoyl and R₁═R₂═CONR₄R₅after purification. To obtain the desired final compounds withR₃=tetrazoyl, N-Me-tetrazoyl and R₁═R₂═COOH after purification, theamide formation steps 2 and 3 are omitted.

General synthetic scheme for the preparation of tricyclic compounds ofthis invention with R³=heteroaryl (e.g., oxadiazolone ortrifluororoxadiazole)

The NH Teoc-protected compounds with R₃═CN and R₁═R₂═COOMe were treatedwith hydroxylamine hydrochloride and a base at elevated temperatures,followed by diethylcarbonate in an appropriate solvent to afford thedesired compounds with R₃=oxadiazolone after purification. In casetrifluoroacetic acid anhydride and base are used in a suitable solventfor step 2 of the above scheme, the desired compounds withR₃═CF₃-oxadiazole are obtained after purification. The compounds withR₃=oxadiazolone and R₃═CF₃-oxadiazole are then treated with base toafford the dicarboxylic acid derivatives. These acids are treated withethylchloroformate, followed by an amine to afford the desired NH-Teocprotected compounds with R₃=oxadiazolone, CF₃-oxadiazole andR₁═R₂═CONR₄R₅ after purification. Cleavage of the Teoc protecting groupwith acid affords the corresponding amine compounds. The reaction ofthese amines with a suitable aldehyde (D-CHO) in an appropriate solventaffords the desired final compounds with R₃=oxadiazolone, CF₃-oxadiazoleand R₁═R₂═CONR₄R₅ after purification.

General synthetic scheme for the preparation of tricyclic compounds ofthis invention with R³=tetrazole and Y═CONR⁴

Anthraquinone derivatives are treated with sodium azide and sulphuricacid in a suitable solvent to yield the desired compounds. Thesecompounds are then treated with alkyl halides and base in a suitablesolvent to obtain the desired compounds after purification. Reaction oftheses compounds with tosylmethyl isocyanide and base in a suitablesolvent, followed by treatment with dibromoethane and potassiumphthalimide affords the desired compounds with R3=CN and R′═N-phthaloylafter purification. The reaction of these compounds withtrimethylsilyl-azide and dibutyltin oxide in a suitable solvent affordsthe compounds with R3=tetrazoyl and R′═N-phthaloyl. Cleavage of theprotecting group with hydrazine hydrate affords the desired amines,which are reacted with a suitable aldehyde (D-CHO) in an appropriatesolvent to afford the desired final compound with R3=tetrazoyl. Thedesired final compound with R₃=tetrazoyl and R₄═H can be obtained byomitting the alkylation step with alkyl halides in the above scheme.

General synthetic scheme for the preparation of compounds with bridgedpiperazinones of this invention with R^(14a,b)=(═O)

A commercially available hydroxyl-proline derivative is treated withbase and alkylated with allylbromide in an appropriate solvent to affordthe allyl-protected amino acid after purification. This compound is thentreated at −30° C. with an appropriate base, triflic anhydride and thenan appropriately protected diamino acid in an appropriate solvent toafford the desired compound after purification. After cleavage of theester moiety with palladium(0) in an appropriate solvent, the compoundis treated with EDCI and base in an appropriate solvent to afford thedesired compound after purification. Cleavage of Fmoc protecting groupby treatment with an suitable base affords the desired product. The freeamine is then treated in the presence of an suitable polymer supportedbase with sulfonyl chlorides, acid chlorides or isocyanates to affordthe desired compounds after purification. Removal of the Boc-protectinggroup with acid in a suitable solvent affords the final desiredcompounds after purification.

Starting with the enantiomers of the amino acid derivatives above, andproceeding through the general procedures as described above, theenantiomeric piperazinone derivatives can be made.

General synthetic scheme for the preparation of compounds with bridgedpiperazinones of this invention with R^(13a,b)=(═O)

After removing the Fmoc group of the commercially available amino acidwith Et₂NH, the primary amine is treated in an appropriate solvent withaldehydes or ketones in a reductive amination reaction to afford thedesired products. Alternatively, the commercially availableN-Boc-protected hydroxy amino acid ester can be treated withtrifluoroacetic acid anhydride. The nucleopHilic displacement reactionof the triflate with commercially available amines affords the desiredproducts, after saponification of the ester moiety with base andpurification. These compounds are then treated with EDCl and a base inan suitable solvent to afford the cyclic amides after purification.These compounds are converted to the desired products by removing theBoc-protection group. These compounds are then reacted in a suitablesolvent with a cyclic sulfamidate, derived from a serine derivative, inthe presence of base. Saponification of the ester of the reactionproduct with a suitable base yields the desired acid compounds afterpurification. Further treatment of the free acids with EDCI in thepresence of an appropriate base and a suitable amine derivative,followed by acidic removal of the Boc-protecting group yields thedesired compounds after purification.

Starting with the enantiomers of the amino acid and amine derivativesabove, and proceeding through the general procedures as described above,the enantiomeric piperazinone derivatives can be made.

General synthetic scheme for the preparation of compounds with bridgedpiperazines of this invention with R^(13a,b) and R^(14a,b)═H

The commercially available bridged piperazine derivate is treated with acommercially available aziridine ester in an appropriate solvent toafford the desired compound after purification. After acidic removal ofthe Boc-protection group, the desired product reacts in presence of abase with an acid chloride or sulfonic acid chloride to yield thedesired products after purification. After basic saponification, thefree acids are treated with EDCI in the presence of an appropriate baseand a suitable amine derivative to afford the desired compounds afterpurification. The Cbz-protecting group is then removed by treatment withTMSI and subsequent purification to afford the desired final compounds.

Starting with the enantiomers of the amine and aziridine derivativesabove, and proceeding through the general procedures as described above,the enantiomeric piperazine derivatives can be made.

As can be seen by the generic schemes, each of the structures of “B”bonds to the “A” structures on its left side and to the “D” structureson its right side as each is depicted below. The compound A-B-D choosesan “A” which includes the following:

A is desirably

The “B” structures are chosen from:

Desirably, B is one of structure (a), (b), (c), and (d). More desirably,B is structure (b)

The “D” structures are chosen from:

The substituents are selected as follows:

E, G, and M represent a three ring system wherein M shares two carbonatoms with each of E and G;

E and G are each independently selected from 6-membered aryl, 5-memberedheteroaryl; 6-membered heteroaryl; a 5-7-membered saturated or partiallysaturated carbocyclic ring; and a 5-7 membered saturated or partiallysaturated heterocyclic ring; desirably E and G are substituted phenyl; Mis a 5-7-membered saturated or partially saturated carboxylic orheterocyclic ring, or a 5-6-membered aromatic or heteroaromatic ring.

E may be substituted with one or more R¹ groups;

G may be substituted with one or more R² groups;

X and Y are divalent and are each independently: a bond, CR⁴R⁵, O, NR⁴,S, S═O, S(═O)₂, C(═O), (C═O)N(R⁴), S(═O)₂N(R⁴), C═N—OR⁴,—C(R⁴R⁵)C(R⁴R⁵)—, —C(R⁴)═C(R⁵)—, —C(R⁴R⁵)NR⁴—, —C(R⁴R⁵)O—,—C(R⁴R⁵)S(═O)_(t)—, —(C═O)O—, —(C═NR^(a))N(R⁴)—, —(C═NR^(a))—,N(C═O)NR⁴NR⁵, N(C═O)R⁴, N(C═O)OR⁴, NS(═O)₂NR⁴NR⁵, NS(═O)₂R⁴; or aryl,heteroaryl, cycloalkyl or heterocyclic ring, all may be optionallysubstituted;

R¹ and R² are each independently: halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂,CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall of which may be optionally substituted. Desirably, R¹ and R² may bedefined independently as —H, —F, —Cl, —CONR⁴R⁵, —CO₂H, —CN or—SO₂NR⁴R⁵R².

R³ is absent or is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴,CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵,NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall of which may be optionally substituted. Desirably, R³ is absent oris —H, —OH, —CO₂H, —CN, —CONR⁴R⁵, R⁵, aryl, NH(C═O)R⁴, NH(SO₂)R⁴,heteroaryl —SO₃H, —PO₃H₂, —CONR⁴R⁵, R⁵, aryl, NH(C═O)R⁴, or NH(SO₂)R⁴,and more desirably, R³ is —CONR⁴R⁵ or tetrazolyl.

R^(a) is hydrogen, CN, NO₂, alkyl, haloalkyl, S(O)_(t)NR⁴R⁵, S(O)_(t)R⁴,C(O)OR⁴, C(O)R⁴, or C(O)NR⁴R⁵;

each occurrence of R⁴, R⁵, R²⁰ and R²¹ are each independently: hydrogen,alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl,heterocycloalkylalkyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl andaminoalkyl are all optionally substituted, or R⁴ and R⁵ when takentogether with the nitrogen to which they are attached complete a 3- to8-membered ring containing carbon atoms and may optionally contain aheteroatom selected from O, S, or NR⁵⁰ and the 3- to 8-membered ring maybe optionally substituted. Desirably, R⁴ and R⁵ are each independently—H or alkyl.

R⁵⁰ is, in each occurrence, R²⁰, CN, NO₂, S(O)_(t)NR²⁰R²¹, S(O)_(t)R²⁰,C(O)OR²⁰, C(O)R²⁰C(═NR^(a))NR²⁰R²¹, C(═NR²⁰)NR²¹R^(a), C(═NOR²⁰)R²¹ orC(O)NR²⁰R²¹;

each occurrence of R⁷ and R⁸ are each independently: halogen, CF₃, COR⁴,OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴,SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵,(C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₁-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall may be optionally substituted. Desirably, R⁷ and R⁸ areindependently H or alkyl.

R⁹ is H or C₁₋₆ alkyl, desirably H.

R¹⁰ is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵,CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵,NR⁴CO₂R⁵, (CO—C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (CO—C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, B(OH)₂, alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl and aminoalkyl are all optionally substituted. Desirably R¹⁰is CN.

R¹¹ and R¹² are each independently: halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂,CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (CO—C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl and aminoalkylall may be optionally substituted;

R^(13a) and R^(13b) are each independently R⁵ or together are ═O;

R^(14a) and R^(14b) are each independently R⁵ or together are ═O;

R^(13c) and R^(14c) are each independently R⁵;

Q^(a) is CH or N;

Q^(b) is CH or N;

U is —C(O)—, —C(═NR⁴)—, —(CR⁴R⁵—)_(p), NR⁵⁰, S(═O)₂, C(═O), (C═O)N(R⁴),N(R⁴)(C═O), S(═O)₂N(R⁴), N(R⁴)S(═O)₂, C═N—OR⁴, —C(R⁴)═C(R⁵)—,—C(R⁴R⁵)_(p)NR⁵⁰—, N(R⁵⁰)C(R⁴R⁵)_(p)—, —O—C(R⁴R⁵)—, —C(R⁴R⁵)S(═O)_(t)—,—(C═O)O—, —(C═NR^(a))N(R⁴)—, —(C═NR^(a))—, N(C═O)NR⁴NR⁵, N(C═O)R⁴,N(C═O)OR⁴, NS(═O)₂NR⁴NR⁵, NS(═O)₂R⁴, or an optionally substituted aryl,heteroaryl, cycloalkyl or heterocyclic ring, all of which may beoptionally substituted. Desirably, U is CH₂.

W is —CH₂—, —S—, —CHF— or —CF₂—;

Z is C or N;

m is 1, or 2;

n is 0, 1, or 2;

p is 0 to 6;

q is 0 to 6; and

t is 0, 1, or 2.

EXAMPLES

Compounds of the present invention having one or more optically activecarbons can exist as racemates and racemic mixtures, diasteromericmixtures and individual diastereomers, enantiomeric mixtures and singleenantiomers, tautomers, atropisomers, and rotamers, with all isomericforms being included in the present invention. Compounds described inthis invention containing olefinic double bonds include both E and Zgeometric isomers. Also included in this invention are all salt forms,polymorphs, hydrates and solvates. All of the above mentioned compoundsare included within the scope of the invention.

The DPP-IV inhibition activity of the DPP-IV inhibitor compounds of thepresent invention may be measured using any suitable assay known in theart. A standard in vitro assay for measuring DPP-IV inhibitor activityis described.

The synthesis of DPP-IV inhibiting compounds of the invention and theirbiological activity assay are described in the following examples whichare not intended to be limiting in any way.

Examples and Methods

All reagents and solvents were obtained from commercial sources and usedwithout further purification. Proton (¹H) spectra were recorded on a 250MHz NMR spectrometer in deuterated solvents. Chromatography wasperformed using Roth silica gel (Si 60, 0.06-0.2 mm) and suitableorganic solvents as indicated in specific examples. For flashchromatography Roth silica gel (Si 60, 0.04-0.063 mm) was used. Thinlayer chromatography (TLC) was carried out on silica gel plates with UVdetection. Preparative thin layer chromatography (Prep-TLC) wasconducted with 0.5 mm or 1 mm silica gel plates (Merck Si 60, F₂₅₄) andthe solvents indicated in the specific examples.

Preparative Example 1

Commercially available prolinamide (5 g) was first treated withbromacetylbromide (4.2 ml) in CH₂Cl₂ and then with trifluoracetic acidanhydride in CH₂Cl₂ as described in WO 98/19998 to afford the titlecompound (7.85 g; 83%). ¹HNMR δ (CDCl₃) 2.05-2.40 (m, 4H), 3.51-3.70 (m,2H), 3.80-3.85 (m, 2H), 4.70-4.86 (m, 1H).

Preparative Example 2

Step A

Commercially available L-prolinamide (25 g) was dissolved in CH₂Cl₂(1200 ml) and triethylamine (30 ml) and 4-dimethylaminopyridine (1.9 g)added. The mixture was cooled to 0° C. and treated with fumaryl chloride(11.7 ml). The dark mixture was stirred at rt for 16 h and cooled to 0°C. TFAA (77 ml) was added dropwise under stirring and the solutionallowed to warm to rt over 6 hours. The reaction mixture was stirred atrt for 1 to 2 days. Ice (500 g) was added followed by cautious additionof sat. NaHCO₃ (600 ml). After the evolution of gas had ceased, theorganic phase was separated and washed with sat. NaHCO₃ (350 ml), H₂O(350 ml), and brine (200 ml). The organic phase was dried over MgSO₄ andconcentrated to afford the title compound (28.6 g; 98%).

¹HNMR δ (CDCl₃) 2.12-2.30 (m, 8H), 3.58-3.69 (m, 2H), 3.73-3.89 (m, 2H),4.72-4.83 (m, 2H), 7.26 (s, 2H).

Step B

The title compound from Step A above (9.6 g) was dissolved in CHCl₃ (90ml) and MeOH (90 ml) and cooled to −78° C. At −78° C. a slow flow ofozone (originating from an O₂ cylinder) was passed through the mixturefor 3 h. The mixture was purged with N₂ and dimethylsulfide (6 ml)added. The mixture was stirred for 1 h, allowed to reach rt andconcentrated. The residue was purified by chromatography on silica(CH₂Cl₂/MeOH, 100:0->92:8) to afford the title compound as a mixture ofthe aldehyde and methoxy hemiacetal in a ratio of ˜1:9 (8.9 g; 69%).

¹HNMR δ (D₂O) 2.10-2.38 (m, 4H), 3.32 (s, 3H), 3.60-3.84 (m, 2H),4.72-4.81 (m, 1H), 5.5 (s, 9/10H), 7.9 (s, 1/10H).

Preparative Example 3

Step A

Commercially available 2-cyano-3-methylpyridine (25 g) was dissolved int-butanol (50 ml) and stirred at 80° C. Concentrated sulphuric acid (25ml) was slowly added over a period of 45 minutes. After completeaddition of the acid stirring was continued at 80° C. for 1 h. Thereaction was diluted with water (50 ml) and toluene (125 ml). The pH wasadjusted to 10 with 25% aqueous ammonia (110 ml). The separated organicphase was concentrated in vacuum affording the desired product (27 g,90%).

¹HNMR δ (CDCl₃) 1.4 (s, 9H), 2.7 (s, 3H), 7.2-7.3 (m, 1H), 7.6 (m, 1H),8.1 (s br, 1H), 8.4 (m, 1H)

Step B

The title compound of Step A (12 g) above was dissolved in THF (150 ml)and cooled to −64° C. n-Butyllithium (1.6 M in hexane, 77 ml) was addedover a period of 30 min. After addition of sodium bromide (0.6 g)stirring was continued for 30 min at −64° C. m-Chlorobenzylchloride (11g) was added while the temperature was kept below −55° C. The mixturewas stirred for 2 hours at −60° C. and for further 2 h at −110° C.Subsequently, the reaction was quenched with water (100 ml) andconcentrated. The aqueous phase was extracted with chloroform (3×100ml). The combined organic phase was dried over MgSO₄ and concentrated invacuum affording the title compound (22 g; 82%).

¹HNMR δ (CDCl₃) 1.4 (s, 9H), 2.9-3.0 (m, 2H), 3.4-3.5 (m, 2H), 7.0-7.4(m, 6H), 8.0 (s br, 1H), 8.4 (m, 1H)

Step C

The title compound of Step B (21.5 g) above was dissolved in phosphorusoxychloride (80 ml) and refluxed for 5 h. The reaction was concentratedand neutralized with 50% aqueous NaOH. The solid was separated andwashed with hot isopropanol to afford the title compound (10.4 g; 63%)

¹HNMR δ (CDCl₃) 2.9-3.0 (m, 2H), 3.0-3.2 (m, 2H), 7.0-7.3 (m, 4H),7.3-7.4 (m, 1H), 7.4-7.5 (m, 1H), 8.5-8.6 (m, 1H)

Step D

The title compound of Step C (10 g) above was dissolved intrifluorosulfonic acid (80 ml) and stirred at 60° C. for 1 h. At rt 6 Naqueous HCl (80 ml) was dropwise added. The reaction was refluxed for 1h and subsequently, poured on ice. After neutralization with 50% aqueousNaOH the precipitate was separated, washed with water and recrystallizedfrom isopropanol/water (3.1) affording the title compound. The motherliquor was concentrated and the residue washed with water and chloroformto afford additional title compound (9.4 g; 94%).

¹HNMR δ (MeOD-d₄) 3.3-3.4 (m, 2H), 3.4-3.5 (m, 2H), 7.5 (m, 2H), 8.1-8.2(m, 2H), 8.7 (d, 1H), 8.9 (d, 1H)

Step E

The title compound of Step D (700 mg) above was dissolved in MeOH (10ml) and cooled to 0° C. NaBH₄ (95 mg) was added in one portion. Themixture was allowed to warm to RT and stirred for 1 h. The reaction wasacidified with 1 N HCl and subsequently, brought to pH 12 with 1 N NaOH.The mixture was poured in water (100 ml) and extracted with CHCl₃ (100ml). The organic phase was dried over MgSO₄ and concentrated affordingthe title compound (705 mg; 100%).

¹HNMR δ (MeOD-d₄) 3.0-3.4 (m, 4H), 6.1 (s, 1H), 7.1.7.3 (m, 3H), 7.5-7.6(m, 2H), 8.3.8.4 (m, 1H)

Step F

The title compound of step E (370 mg) above was dissolved in toluene (5ml) and cooled to −15° C. Thionyl chloride (286 mg) was slowly added andthe reaction was allowed to come to RT and run overnight. The solutionwas neutralized with triethylamine and directly used in the next step.

Preparative Example 4

Step A

The title compound from Preparative Example 3 Step E (285 mg) wasdissolved in ethanol (10 ml) and 10% Pd/C (100 mg) and ammonium formiate(916 mg) were added. The mixture was refluxed for 2 h. Subsequently, thereaction was treated with water (20 ml) and extracted twice withchloroform (50 ml). The combined organic phase was dried over MgSO₄ andconcentrated. The residue was purified by chromatography on silica(EtOAc/cyclohexane 1:4) to afford the title compound (200 mg; 82%).

¹HNMR δ (MeOD-d₄) 2.9-3.1 (m, 2H), 3.3-3.6 (m, 2H), 6.3 (s, 1H), 7.0-7.3(m, 4H), 7.4 (m, 1H), 7.8 (m, 1H), 8.3 (m, 1H)

Step B

The title compound of Step A (200 mg) above was dissolved in toluene (5ml) and cooled to −15° C. Thionyl chloride (235 mg) was slowly added andthe reaction was allowed to come to RT and run overnight. The solutionwas neutralized with triethylamine directly used.

Preparative Example 5

To a cooled solution (12° C.) of commercially available ethylenediamine(30 ml) was added within 5 min commercially availabledibenzosuberylchloride (3.3 g). The mixture was stirred at rt for 1 hand then K₂CO₃ (5.8 g) was added. After an additional 30 min at rt, themixture as filtered, the salts washed with 5 ml ethylenediamine and thefiltrates concentrated. The residue was dissolved in 80 ml EtOAc, 20 mlH₂O and 5 ml NH₄OH-solution (25%). The organic phase was separated,dried over MgSO₄ and concentrated to afford the title compound (3.4 g;93%; MH⁺=253).

Preparative Example 6-9

The title compounds from Preparative Example 6 to 9 were preparedaccording to the procedure described in Preparative Example 5 using thechlorides and amines as indicated in the Table below. In case thechlorides did not dissolve in the amines after 10 Min, CH₃CN or THF wasadded until a clear solution was obtained.

Preparative 1. Yield Example Chloride Amine Product 2. MH⁺ 6

NH₄OH

1. 61% 2. ¹H-NMR δ (CDCl₃) 2.0 (s, 2H), 3.10-3.24 (m, 2H), 3.31-3.45 (m,2H), 5.43 (s, 1H), 7.10-7.19 (m, 6H), 7.36-7.41 (m, 2H) 7

1. 97% 2. 281 8

1. 60% 2. 288 9

1. 78% 2. ¹H-NMR δ (CD₃OD) 2.6-2.8 (m, 4H), 3.0-3.2 (m, 2H), 3.3-3.6 (m,2H), 5.2 (s, 1H), 7.1-7.2 (m, 4H), 7.3-7.4 (m, 1H), 7.5 (m, 1H), 8.2-8.3(m, 1H)

Preparative Example 10

Step A

Commercially available dibenzosuberylchloride (300 mg) and4-N-Boc-amino-piperidine (290 mg) were suspended in CH₃CN (10 ml). After10 min K₂CO₃ (545 mg) was added and the mixture was stirred at rt for 3h. The mixture was diluted with EtOAc (30 ml) and H₂O (15 ml), theorganic phase separated, dried over MgSO₄ and concentrated to afford thetitle compound (460 mg; 89%; MH⁺=393).

Step B

The title compound from Step A above (460 mg) was dissolved in asolution of 4 M HCl in dioxane (20 ml). The mixture was stirred at rtfor 2 h and concentrated to afford the title compound (335 mg; 97%;MH⁺=293).

Preparative Example 11-12

The title compounds from Preparative Example 11 and 12 were preparedaccording to the procedure described in Preparative Example 10 using thechlorides and amines as indicated in the Table below.

Preparative 1. Yield Example Chloride Amine Product 2. MH⁺ 11

1. 64% 2. 279 12

1. 56% 2. 265

Preparative Example 13

Step A

To a suspension of AgCN (4.7 g) in CH₃CN (60 ml) under nitrogen wasadded at rt a solution of commercially available dibenzosuberylchloride(6 g) in CH₃CN (60 ml) and benzene (10 ml). The mixture was heated atreflux for 2 h, cooled to rt and filtered. The salts were washed with 20ml CH₃CN and the filtrates concentrated. The residue was purified bychromatography on silica (EtOAc/cyclohexane, 1:9) to afford the titlecompound (5 g; 87%; MNa⁺=242).

Step B

A suspension of LiAlH₄ (360 mg) in Et₂O (20 ml) was slowly treated witha solution of AlCl₃ (950 mg) in Et₂O (20 ml). The mixture was stirred atrt for 10 min and then the title compound from Step A above (1.03 g) wasadded within 5 min. The mixture was stirred at rt for 10 min and thenrefluxed for 8 h. After the addition of H₂O (20 ml) and 25% NH₄OH (6ml), the mixture was filtered and the salts washed with H₂O (20 ml) andEt₂O (10 ml). The organic phase was separated, dried over MgSO₄ andconcentrated to afford the title compound (157 mg; 15%; MH⁺=224).

Preparative Example 14

Step A

To a solution of commercially available iminodibenzyl (5 g) in toluene(25 ml) was added commercially available bromoacetylbromide (4.35 ml).The mixture was heated under reflux for 2 h 30 Min, cooled andconcentrated. A portion of the crude product (800 mg) was dissolved inDMA (6 ml) and treated with NaN₃ (815 mg). The mixture was heated at60-70° C. overnight and diluted with EtOAc (30 ml) and H₂O (10 ml). Theorganic phase was separated, dried over MgSO₄ and concentrated. Theresidue was treated with EtOAc/cyclohexane (1:9) (2 ml), sonicated for 2min and the solvents removed by syringe. The residue was dried to affordthe title compound (483 mg; 69%; MH⁺=279).

Step B

The title compound from Step A above (483 mg) was dissolved in MeOH (25ml) and 10% Pd/C (100 mg) added. The mixture was hydrogenated for 1 h,filtered and the catalyst washed with MeOH (10 ml). The filtrates wereconcentrated and the residue purified by chromatography on silica(CH₂Cl₂/MeOH, 9:1) to afford the title compound (415 mg; 95%; MH⁺=253).

Step C

To a suspension of LiAlH₄ (242 mg) in THF (6 ml) was added a solution ofthe title compound from Step B above (322 mg) in THF (6 ml). The mixturewas heated under reflux for 2 h 30 min. The mixture was cooled to 0° C.,quenched with H₂O (0.3 ml) and diluted with 15% NH₄OH-solution (0.3 ml)and H₂O (0.8 ml). The mixture was stirred at rt for 45 Min, filtered andthe salts washed with THF (8 ml). The filtrates were concentrated andthe residue purified by chromatography on silica (CH₂Cl₂/MeOH, 9:1) toafford the title compound (79 mg; 26%; MH⁺=239).

Preparative Example 15

Step A

A mixture of commercially available dibenzosuberenol (1.5 g) and malonicacid (830 mg) was heated at 160-170° C. for 2 h. A mixture of H₂O (5 ml)and 0.1 M HCl (5 ml) was added and the mixture cooled to rt. The mixturewas diluted with EtOAc (100 ml) and H₂O (10 ml), the organic phaseseparated, dried over MgSO₄ and concentrated. The residue was purifiedby chromatography on silica (CH₂Cl₂/acetone, 98:2->CH₂Cl₂/acetone, 9:1)to afford the title compound (775 mg; 43%; MNa⁺=273).

Step B

A mixture of title compound from Step A above (775 mg) and triethylamine(0.59 ml) in THF (20 ml) was cooled to −40° C. and treated withisobutylchloroformate. After stirring at −40° C. for 1 h, the mixturewas filtered and the salts washed with THF (5 ml). The filtrates werethen treated at 0° C. with 25% NH₄OH (15 ml) for 1 h 30 min. The mixturewas diluted with EtOAc (60 ml), the organic phase separated, dried overMgSO₄ and concentrated. The residue was treated with CHCl₃ (1.5 ml), thesolvent removed by syringe and the residue dried to afford the titlecompound (677 mg; 88%; MH⁺=250).

Step C

To a suspension of LiAlH₄ (513 mg) in THF (15 ml) was added a solutionof the title compound from Step B above (677 mg) in THF (25 ml). Themixture was heated under reflux for 2 h. The mixture was cooled to 0°C., quenched with H₂O (0.65 ml) and diluted with 4 M NaOH-solution (2.5ml). The mixture was stirred at rt for 45 Min, filtered and the saltswashed with THF (15 ml). The filtrates were concentrated and the residuepurified by chromatography on silica (CH₂Cl₂/MeOH, 9:1) to afford thetitle compound (560 mg; 88%; MH⁺=236).

Step D

The title compound from Step C above (350 mg) was dissolved in MeOH (15ml) and 10% Pd/C (300 mg) and 1 M HCl (1.5 ml) were added. The mixturewas hydrogenated overnight, filtered and the catalyst washed with MeOH(10 ml). The filtrates were concentrated and the residue dissolved inEtOAc (30 ml) and sat. NaHCO₃ (10 ml). The organic phase was separatedand the aqueous phase extracted with EtOAc (20 ml). The combined organicphase was dried over MgSO₄ and concentrated to afford the title compound(232 mg; 66%; MH⁺=238).

Preparative Example 16

Step A

The intermediate from Preparative Example 14 Step A (1 g) was dissolvedin DMA (6 ml) and treated with NaCN (368 mg). The mixture was heated at60-70° C. overnight and diluted with EtOAc (50 ml) and H₂O (15 ml). Theorganic phase was separated, dried over MgSO₄ and concentrated. Theresidue was purified by chromatography on silica (CH₂Cl₂/acetone, 98:2)to afford the title compound (282 mg; 34%; MH⁺=263).

Step B

To a suspension of LiAlH₄ (123 mg) in THF (6 ml) was added a solution ofthe title compound from Step A above (282 mg) in THF (6 ml). The mixturewas heated at 50° C. for 2 h, cooled to 0° C. and treated with H₂O (0.2ml) and 4 M NaOH (0.8 ml). The mixture was stirred at rt for 45 Min,treated with MgSO₄ and filtered. The filtrate was concentrated and theresidue purified by chromatography on silica (CH₂Cl₂/MeOH,95:5->CH₂Cl₂/MeOH, 9:1) to afford the title compound (32 mg; 12%;MH⁺=253).

Preparative Example 17

Step A

To a suspension of magnesium (701 mg) in Et₂O (7 ml) was slowly addedethylbromide (2.15 ml). After the formation of the Grignard reagent, themixture was cooled to 5° C. and a solution of diethylamine (3 ml) inEt₂O (5 ml) was slowly added. The mixture was refluxed for 30 Min,cooled to 5° C. and treated with a mixture of commercially availabledibenzosuberone (3 g) and tert-butylacetate (1.95 ml) in Et₂O (15 ml).The mixture was heated under reflux for 2 h, cooled to rt and pouredonto ice-water containing an excess of NH₄Cl. The mixture was extractedwith CH₂Cl₂ (3×100 ml), the organic phase dried over MgSO₄ andconcentrated. The residue was purified by chromatography on silica(EtOAc/cyclohexane, 1:9) to afford the title compound (3.5 g; 75%;MNa⁺=347).

Step B

To a suspension of LiAlH₄ (346 mg) in THF (12 ml) was added a solutionof the title compound from Step A above (2 g) in THF (12 ml). Themixture was heated under reflux for 2 h, cooled to 0° C. and treated 4 MNaOH (4.5 ml). The mixture was stirred at rt for 45 min and filtered.The filtrate was concentrated and the residue dissolved in EtOAc (100ml), H₂O (10 ml) and sat. NH₄Cl (10 ml). The organic phase wasseparated, dried over MgSO₄ and concentrated. The residue was purifiedby chromatography on silica (EtOAc/cyclohexane, 3:7) to afford the titlecompound (937 mg; 60%; MNa⁺=277).

Step C

The title compound from Step B above (937 mg) was dissolved in benzene(1.5 ml) and pyridine (1.5 ml). The mixture was cooled to 5° C. andtreated with a solution of p-tosylchloride in benzene (1.5 ml). Themixture was stirred at rt for 7 h, diluted with EtOAc (40 ml) and washedwith 0.1 M HCl (10 ml), sat. NaHCO₃ (10 ml) and brine (10 ml). Theorganic phase was separated, dried over MgSO₄ and concentrated. Thecrude intermediate was dissolved in DMA (9 ml) and treated with NaN₃(1.2 g). The mixture was heated at 70° C. overnight and the DMA removed.The residue was dissolved in EtOAc (50 ml), sat. NaHCO₃ (10 ml) andbrine (10 ml). The organic phase was separated, dried over MgSO₄ andconcentrated. The residue was purified by chromatography on silica(EtOAc/cyclohexane, 1:4) to afford the title compound (704 mg; 68%;MNa⁺=302).

Step D

The title compound from Step C above (200 mg) was dissolved in MeOH (8ml) and 10% Pd/C (40 mg) added. The mixture was hydrogenated for 1 h 30Min, filtered and the catalyst washed with MeOH (10 ml). The filtrateswere concentrated to afford the title compound (175 mg; 96%; MH⁺=254).

Step E

The title compound from Step D above (75 mg) was dissolved in EtOH (1ml) and a 4 M solution of HCl in dioxane (1 ml) added. The mixture wasstirred at rt for 12 h and concentrated. The residue was dissolved inEtOAc (20 ml) and sat. NaHCO₃ (5 ml). The organic phase was separated,dried over MgSO₄ and concentrated to afford the title compound (67 mg;96%; M⁺—NH₃=219).

Preparative Example 18

Step A

The title compound from Preparative Example 13 Step A (1.1 g) wasdissolved in THF (5 ml) and added to a suspension of NaH (132 mg) in THF(5 ml). The mixture was heated under reflux for 1 h, cooled to rt andtreated with 1,2-dibromoethane (0.9 ml) in THF (1 ml). The mixture washeated under reflux for 4 h, cooled to rt and filtered. The salts werewashed with THF (5 ml) and the filtrates concentrated. The residue wasdissolved in DMA (12 ml) and treated with NaN₃ (1.6 g). The mixture washeated at 60-70° C. overnight and the DMA removed. The residue wasdissolved in EtOAc (40 ml) and H₂O (10 ml), the organic phase separated,dried over MgSO₄ and concentrated. The residue was purified bychromatography on silica (EtOAc/cyclohexane, 1:9) to afford the titlecompound (1.14 g; 78%; MH⁺=289).

Step B

The title compound from Step A above (510 mg) was dissolved in MeOH (20ml) and 10% Pd/C (150 mg) and 2 M HCl (0.9 ml) added. The mixture washydrogenated for 1 h 30 Min, filtered and the catalyst washed with MeOH(10 ml). The filtrates were concentrated and the residue purified bychromatography on silica (CH₂Cl₂/MeOH, 95:5 to CH₂Cl₂/MeOH, 4:1) toafford a mixture of the title compound and the cyclic amidine (450 mg;96%; MH+=263).

Step C

The title compounds from Step B above (350 mg) were treated with 2 ml57% H₂SO₄. The mixture was heated at 100° C. for 3 h, cooled to rt anddiluted with H₂O (10 ml). The mixture was made alkaline (pH˜11) byadding 10% NaOH and extracted with EtOAc (3×30 ml). The organic phasewas dried over MgSO₄ and concentrated. The residue was purified bychromatography on silica (CH₂Cl₂/MeOH, 9:1 to CH₂Cl₂/MeOH (7 M NH₃),9:1) to afford a mixture of the title compound and the cyclic amidine(223 mg; 60%; MH⁺=281).

Preparative Example 19

Step A

Commercially available (S)-2-aminopropan-1-ol (2.0 g) was dissolved inCH₂Cl₂ (20 ml) and Boc₂O (6.4 g) was added. After stirring for 4 h atroom temperature the solvent was removed to afford the title compound(4.7 g, 99%).

¹H-NMR δ (CDCl₃): 1.10 (s, 3H), 1.50 (s, 9H), 2.40 (s, 1H), 3.45-3.70(m, 2H), 3.75-3.80 (m, 1H), 4.80 (s, 1H).

Step B

Imidazole (4.1 g) was dissolved in CH₂Cl₂ (50 ml) and cooled to 0° C.Thionyl chloride (1.3 ml) dissolved in CH₂Cl₂ (10 ml) was added dropwiseand the resulting suspension was allowed to warm to rt. Stirring wascontinued for 1 h at rt and then the mixture was cooled to −78° C. Asolution of the title compound from Step A above (1.8 g) in CH₂Cl₂ (50ml) was added over a period of 1 h and the resulting mixture was allowedto warm to rt and stirred overnight. The mixture was filtered throughcelite and the filter aid was washed well with CH₂Cl₂. The organic phasewas diluted with CH₂Cl₂, washed with water and brine, dried over MgSO₄,filtered and concentrated to a volume of approx. 100 ml.

A solution of NaIO₄ (4.3 g) in water (100 ml) was added and the mixturewas cooled to 0° C. Ru(IV)O₂ hydrate (150 mg) was added and the blacksuspension was stirred for 2 h at 0° C. It was then warmed to rt andstirred overnight. The mixture was filtered through celite and thefiltrate was extracted with CH₂Cl₂. The combined organic phase waswashed with brine, dried and filtered. Treatment of the filtrate withactivated charcoal (2 g) for 30 min removed traces of ruthenium. Themixture was filtered again and evaporated to yield the title compound(1.5 g, 63%).

¹H-NMR δ (CDCl₃): 1.45 (s, 3H), 1.49 (s, 9H), 4.14 (dd, 1H), 4.29-4.42(m, 1H), 4.61 (dd, 1H).

Preparative Example 20

The title compound from Preparative Example 20 was prepared according tothe procedure described in Preparative Example 19 using the aminoalcoholas indicated in the Table below.

Prepar- ative Exam- 1. Yield ple Aminoalcohol Product 2. ¹H-NMR 20

1. 69% 2. ¹H-NMR δ (CDCl₃): 1.45 (s, 3 H), 1.49 (s, 9 H), 4.14 (dd, 1H), 4.29-4.42 (m, 1 H), 4.61 (dd, 1 H).

Preparative Example 21

Step A

To a stirred solution of the commercially available 2-(S)-amino propanol(17.4 g) in water (200 ml) was added a solution of triethylamine (32 ml)in dioxane (200 ml). To the solution was added commercially available1-[2-(Trimethylsilyl)ethoxy-carbonyloxy]pyrrolidin-2,5-dione (60 g). Themixture was stirred at rt overnight, then diluted with water (200 ml),acidified with 1 N HCl, and extracted with Et₂O (2×500 ml). The combinedorganic phase was washed with brine, dried over MgSO₄ and evaporated toafford the title compound (44.2 g; 87%).

¹H-NMR δ (CDCl₃): 0.02 (s, 9H), 0.90-1.05 (m, 2H), 1.20 (d, 3H), 2.80(br s, 1H), 3.40-3.80 (m, 3H), 4.10-4.20 (m, 2H), 4.85 (s, 1H).

Step B

Imidazole (96 g) was dissolved in CH₂Cl₂ (1200 ml) and cooled to 0° C.Thionyl chloride (30.8 ml) was diluted with CH₂Cl₂ (600 ml) and addeddropwise. The resulting suspension was allowed to warm to rt. Stirringwas continued for 1 h at rt and then the mixture was cooled to −78° C. Asolution of the title compound from Step A above (44.2 g) in CH₂Cl₂(1200 ml) was added over a period of 1 h and the resulting mixture wasallowed to warm to rt and stirred overnight. The mixture was filteredthrough celite, the filter aid was washed well with CH₂Cl₂. The organicphase was washed with water (2×700 ml), dried over MgSO₄, filtered andconcentrated to a volume of approx. 1000 ml.

A solution of NaIO₄ (100 g) in water (1000 ml) was added and the mixturewas cooled to 0° C. RuO₂×H₂O (1 g) was added and the black suspensionwas stirred for 2 h at 0° C. It was then warmed to rt and stirredovernight. The phases were separated and the organic phase was treatedwith granulated charcoal (˜20 g). The mixture was stirred for approx. 1h, filtered through celite and the filtrate was dried with MgSO₄,filtered and evaporated to yield the title compound (50.7 g, 89%).

¹H-NMR δ (CDCl₃): 0.02 (s, 9H), 1.00-1.15 (m, 2H), 1.50 (d, 3H), 4.15(dd, 1H), 4.35-4.45 (m, 3H), 4.65 (dd, 1H).

Preparative Example 22-23

Following a similar procedure as that described in Preparative Example21 but using the aminoalcohols as indicated in the Table below, thetitle compounds were obtained.

Prepar- ative Exam- 1. Yield ple Aminoalcohol Product 2. ¹H-NMR 22

1. 58% 2. ¹H-NMR δ (CDCl₃): 0.02 (s, 9 H), 1.00-115 (m, 2 H), 4.00-4.10(m, 2 H), 4.25-4.40 (m, 2 H), 4.55-4.65 (m, 2 H). 23

1. 32% (M + Na)⁺ = 318

Preparative Example 24-46

If one were to follow a similar procedure as that described inPreparative Example 21 but using the aminoalcohols as indicated in theTable below, one would obtain the desired products.

Prepar- ative Example Aminoalcohol Product 24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

Preparative Example 47

Step A

A suspension of NaH (132 mg) in THF (10 ml) was added to a solution ofPreparative Example 13 Step A (1.1 g) in THF (20 ml) and heated at 60°C. for 1 h. Then the mixture was cooled to 0° C. and a solution ofPreparative Example 19 (1.2 g) in THF (10 ml) was added. The suspensionwas heated at 60° C. for 4 h and then diluted with ethyl acetate. Theorganic phase was washed with water, brine and dried over MgSO₄. Removalof the solvents and column chromatography (EtOAc/hexane, 1:4) afford thetitle compound (1.7 g, 90%, MH⁺=377).

Step B

The title compound from Step A above (1.5 g) was dissolved in 57% H₂SO₄and the solution was heated at 100° C. for 2 h. The mixture was dilutedwith water and extracted with ethyl acetate. The organic phase wasdiscarded and 50%-aqueous KOH solution added to the aqueous phase untilpH>8. The aqueous phase was extracted with ethyl acetate (2×75 ml). Theorganic phase was washed with water, brine, dried over MgSO₄ andevaporated to afford the title compound. (600 mg, 53%).

¹H-NMR δ (CDCl₃): 0.95 (d, 3H), 1.82 (s, 2H), 2.37-2.58 (m, 2H),2.82-2.92 (m, 1H), 3.18 (s, 4H), 5.60 (s, 2H), 7.08-7.24 (m, 6H),7.40-7.48 (m, 2H).

Preparative Example 48

The title compound was prepared according to the procedure described inPreparative Example 47 using the sulfamidate from Preparative Example 20as indicated in the Table below.

Preparative 1. Yield Example Nitrile Sulfamidate Product 2. ¹H-NMR 48

1. 80% 2. ¹H-NMR δ (CDCl₃): 0.95 (d, 3 H), 1.82 (s, 2 H), 2.37-2.58 (m,2 H), 2.82-2.92 (m, 1 H), 3.18 (s, 4 H), 5.60 (s, 2 H), 7.08-7.24 (m, 6H), 7.40-7.48 (m, 2 H).

Preparative Example 49

Step A

Commercially available 2,5-dibromotoluene (8.28 ml) was dissolved inhexane (90 ml) and treated with a 1.6 M solution of butyllithium inhexane (160 ml). The mixture was heated at 60° C. for 20 h, cooled to rtand poured onto a mixture of dry ice in Et₂O (750 ml). The mixture wasallowed to warm to rt, filtered and the precipitate washed with 90 mlEt₂O. The precipitate was titrated with 140 ml glacial acetic acid toafford the title compound (10 g; 92%).

¹H-NMR δ (DMSO-d₆) 2.58 (s, 3H), 7.80-7.90 (m, 3H)

Step B

The title compound from Step A above (13 g) was suspended in MeOH (300ml) and slowly treated with thionyl chloride (15.7 ml). The mixture washeated under reflux for 2 h to become a clear solution. The solventswere concentrated to afford the title compound (13.3 g; 88%; MH⁺=209).

Step C

The title compound from Step B above (13.3 g) was dissolved in CCl₄ (500ml) and commercially available N-bromosuccinimide (10.7 g) added. Themixture was heated to 80° C. and commercially available AIBN (327 mg)added. The mixture was then irradiated with a 100 W light bulb andheated at 100-105° C. for 2 h 30 min. The cooled mixture was filteredand the precipitate washed with 50 ml CCl₄. The filtrates wereconcentrated and the residue dissolved in CH₃CN (180 ml). The mixturewas treated with triphenylphosphine (16 g) and heated under reflux for 3h. The mixture was concentrated to ˜100 ml and Et₂O (500 ml) added. Themixture was allowed to stand at rt for 30 Min, filtered and theprecipitate washed with Et₂O (30 ml) to afford the title compound (20 g;57%).

Step D

The title compound from Step C above (20 g) was suspended in CH₃CN (160ml) and commercially available 4-Fluorobenzaldehyde (5.4 ml) added. Themixture was then treated with commercially available DBN (10 ml) andheated at 100° C. for 1 h. The mixture was concentrated to half itsvolume and poured into H₂O (150 ml). The mixture was extracted withEtOAc (2×150 ml), the organic phase washed with 5% HCl (2×75 ml), driedover MgSO₄ and concentrated. The residue was suspended in H₂O (240 ml)and MeOH (20 ml) and KOH (20 g) added. The mixture was heated at 100° C.for 16 h, cooled to rt and washed with CH₂Cl₂ (3×75 ml). The aqueousphase was acidified (pH˜1) by adding conc. HCl, filtered, theprecipitate washed with H₂O (20 ml) and air-dried. The residue wasdissolved in MeOH (900 ml) and 10% Pd/C (1.5 g) added. The mixture washydrogenated for 1 h, filtered, the catalyst washed with MeOH (50 ml)and concentrated to afford the title compound (8.6 g; 82%; MH⁺=289).

Step E

The title compound from Step D above (1.44 g) was suspended in sulfolane(9 ml) and treated with polyphosphoric acid (30 g). The mixture washeated under N₂ at 170-175° C. for 3 h and poured onto ice-water (150ml). The mixture was stirred at rt for 1 h, extracted with EtOAc (2×150ml), dried over MgSO₄ and concentrated. The residue was dissolved inMeOH (20 ml) and treated with thionyl chloride (1 ml). The mixture washeated under reflux for 1 h and concentrated. The residue was dissolvedin Et₂O (100 ml) and washed with sat. NaHCO₃ (30 ml) and brine (30 ml).The organic phase was separated, dried over MgSO₄ and concentrated. Theresidue was purified by chromatography on silica (CH₂Cl₂) to afford thetitle compound (960 mg; 67%; MH⁺=285).

Step F

The title compound from Step E (1420 mg) was dissolved in CHCl₃ (20 ml)and MeOH (20 ml) and treated with NaBH₄ (230 mg). The mixture wasstirred at rt for 1 h and poured onto ice-water (150 ml). The mixturewas extracted with EtOAc (2×150 ml), the organic phase dried over MgSO₄and concentrated to afford the title compound (1420 mg; 99%, M⁺+Na=309).

Step G

The title compound from Step F above (1420 mg) was dissolved in THF (20ml) and treated with thionyl chloride (0.91 ml). The mixture was stirredat rt for 16 h and concentrated without heating. The residue wasdissolved in CH₃CN (17 ml) and treated with AgCN (785 mg). The mixturewas heated at 90° C. for 2 h 30 Min, filtered and the salts washed withCH₃CN (40 ml). The filtrates were concentrated and the residue purifiedby chromatography on silica (CH₂Cl₂) to afford the title compound (1160mg; 79%; MH⁺=296).

Step H

The title compound from Step G above (1327 mg) was dissolved in degassedTHF (15 ml) and added to a suspension of NaH (119 mg) in degassed THF (5ml). The mixture was heated at 90° C. for 1 h 15 min and cooled to rt.The mixture was then treated with 1,2-dibromoethane (0.81 ml) in THF (1ml) and the mixture was heated at 90° C. for 4 h 30 min. The mixture wascooled to rt, diluted with 100 ml EtOAc, 10 ml brine and 10 ml sat.NH₄Cl. The organic phase was separated, dried over MgSO₄ andconcentrated. The residue was dissolved in DMA (10 ml) and treated withNaN₃ (720 mg). The mixture was heated at 60° C. for 16 h and dilutedwith EtOAc (100 ml) and brine (15 ml). The organic phase was separated,washed with 0.1 m HCl (15 ml) and brine (15 ml). The organic phase wasdried over MgSO₄, concentrated and the residue purified bychromatography on silica (EtOAc/cyclohexane, 1:4) to afford the titlecompound (931 mg; 57%; MH⁺=365).

Step I

The title compound from Step H above (1050 mg) was dissolved in MeOH (40ml). The mixture was treated with concentrated HCl (0.25 ml) and 10%Pd/C (250 mg). The mixture was hydrogenated for 1 h, filtered and thecatalyst washed with MeOH (20 ml). The filtrates were concentrated toafford a mixture of the title compound and the cyclic amidine in a 9:1ratio (950 mg; 97%; MH⁺=339).

Step J

The title compounds from Step I above (950 mg) were treated with 57%H₂SO₄ (5 ml) and heated under N₂ at 90° C. for 3 h. The mixture wascooled, diluted with H₂O (80 ml) and made alkaline (pH˜10) by adding 50%NaOH. The mixture was washed with EtOAc (20 ml) and the aqueous phasediluted with dioxane (40 ml). The mixture was treated with an excess ofBoc₂O and stirred at rt for 16 h while the pH was kept at pH˜10.0. Themixture was acidified to pH˜4.0 by adding 1 M HCl and extracted withEtOAc (2×150 ml). The organic phase was dried over MgSO₄ andconcentrated. The residue was purified by chromatography on silica(CH₂Cl₂/MeOH, 9:1) to elute the cyclic amidine side product, followed byCH₂Cl₂/MeOH (4:1) to afford the title compound (282 mg, 23%; MNa⁺=465).

Step K

The title compound from Step J above (135 mg) was dissolved in THF (6ml) and triethylamine (0.056 ml). The mixture was cooled to −40° C. andtreated with ethyl chloroformate (0.031 ml). The mixture was stirred at−40° C. for 1 h, diluted with 4 ml THF and treated at 0° C. with 33%aqueous ammonia solution (10 ml). The mixture was stirred at 0° C. for 1h and then 1 h at rt. The mixture was diluted with EtOAc (80 ml) andwashed with brine (25 ml), sat. NH₄Cl (25 ml and brine (25 ml). Theorganic phase was dried over MgSO₄ and concentrated. The residue waspurified by chromatography on silica (CH₂Cl₂/MeOH, 9:1) to afford thetitle compound (97 mg, 72%, MNa⁺=464).

Step L

The title compound from Step K above (94 mg) was treated with 4 Msolution of HCl in dioxane (2.5 ml) and the flask was agitated for 30min. The mixture was concentrated and the residue dissolved in 5 ml H₂O.The mixture was filtered through a Millex VV (0.1 μM) filter unit andthe filtrate concentrated to afford the title compound (65.8 mg, 82%,MH⁺=342).

Preparative Example 50

Step A

The title compound from Preparative Example 13 Step A (3.3 g) wasdissolved in THF (5 ml) and slowly added to a suspension of NaH (540 mg)in THF (10 ml). The mixture was heated at reflux for 30 min, cooled tort and treated with 1,2-dibromoethane (4 ml). The reaction was stirredat 60° C. overnight, cooled to rt and filtered. The solvent was removedaffording the title compound (4.8 g; 98%)

¹HNMR δ CDCl₃ 2.9-3.2 (m, 6H), 3.2-3.4 (m, 2H), 7.1-7.3 (m, 6H), 7.9-8.0(m, 2H)

Step B

The title compound from Step A above (1.5 g) and potassium phthalimide(13.8 g) were suspended in DMF (20 ml) and stirred at 100° C. overnight.The precipitate was removed and the reaction was concentrated in vacuum.Chromatography of the residue on silica (EtOAc/cyclohexane) afforded thetitle compound (1.4 g; 78%).

¹HNMR δ CDCl₃ 2.8-2.9 (m, 2H), 3.0-3.2 (m, 2H), 3.4-3.6 (m, 2H), 3.6-3.8(m, 2H), 7.1-7.3 (m, 6H), 7.6-7.7 (m, 2H), 7.7-7.8 (m, 2H), 7.9-8.0 (m,2H)

Step C

The title compound from Step B above (1.40 g) was dissolved in toluene(30 ml) and treated with dibutyltin oxide (446 mg) andtrimethylsilylazide (2.3 ml). The mixture was heated under a N₂atmosphere at 90° C. overnight. Additional dibutyltin oxide (200 mg) andtrimethylsilylazide (2.3 ml) were added and the reaction was continuedfor 24 h at 90° C. The solvent was removed and the residue was treatedwith EtOAc (30 ml) and 1 N HCl (30 ml) at 50° C. for 1 h. The phaseswere separated and the organic phase was concentrated. The residue waspurified by chromatography on silica (EtOAc/cyclohexane) to afford thetitle compound (600 mg, 39%, MH⁺=436).

Step D

The title compound from Step C above (200 mg) was dissolved in ethanol(5 ml) and treated with hydrazine hydrate (100 mg) at rt. The solutionwas heated at 80° C. for 2 h and then stirred for 1 h at rt. Thereaction was filtered and the filtrate was concentrated. The residue wastreated with CHCl₃ and filtered again. The filtrate was concentrated toafford the title compound (60 mg, 43%, MH⁺=306).

Preparative Example 51

Step A

Commercially available 2-bromo-4-fluorotoluene (5 g) was diluted withdiethyl ether (10 ml). About ⅓ of the resulting solution was added tomagnesium turnings (761 mg) which were overlayed with Et₂O (25 ml). Theremaining 2-bromo-4-fluorotoluene solution was added dropwise after thereaction started. The reaction was kept at reflux for 2 h. The Grignardreagent was poured onto a mixture of crushed dry ice in Et₂O (750 ml).The resulting mixture was allowed to warm to rt. The solvent wasremoved, the resulting residue was treated with EtOAc (100 ml) andextracted with aqueous 1 N HCl (100 ml). The organic phase was driedover MgSO₄, filtered and concentrated to afford the title compound (2.3g; 56%).

¹H-NMR δ CDCl₃ 2.5 (s, 3H), 7.0-7.2 (m, 2H), 7.7 (m, 1H)

Step B

The title compound from Step A above (2.3 g) was dissolved in THF (50ml). Methyl iodide (0.95 ml) and N,N-diisopropylethylamine (3.2 ml) wereadded. The reaction was stirred at rt for 2 h. The reaction mixture wasfiltered and concentrated to afford the title compound (2.3 g; 90%).

¹H-NMR δ CDCl₃ 2.6 (s, 3H), 3.9 (s, 3H), 7.0-7.2 (m, 2H), 7.6-7.7 (m,1H)

Step C

The title compound from Step B above (8.9 g) and commercially availableN-bromosuccinimide (14 g) were suspended in CCl₄ (500 ml). The mixturewas heated to 80° C. and AIBN (270 mg) added. The mixture was irradiatedwith a 100 W light bulb and heated at 100-105° C. for 3.5 h. The cooledmixture was filtered. The filtrate was concentrated and the residuedissolved in CH₃CN (150 ml). The mixture was treated withtriphenylphosphine (14 g), heated under reflux for 3 h and thenconcentrated. The residue was suspended in CH₃CN (160 ml) and treatedwith commercially available 3-fluorobenzaldehyde (6.5 g) and DBN (13ml). The mixture was heated under reflux for 3 h. The reaction wasconcentrated to half its volume and poured into H₂O (150 ml). Themixture was extracted with EtOAc (3×150 ml), the organic phase separatedand concentrated. The residue was suspended in 1:1 H₂O/MeOH-mixture (100ml) and treated with KOH (30 g). The mixture was stirred at 60° C.overnight, cooled to rt and washed with CHCl₃ (3×100 ml). The aqueousphase was acidified (pH˜1) by adding conc. HCl and extracted with EtOAc.The organic phase was separated and concentrated. The crude residue wassuspended in sulfolane (20 ml) and treated with polyphosphoric acid (25g). The mixture was heated under N₂ at 200° C. for 2 h, poured ontoice-water (150 ml) and stirred at rt overnight. The mixture wasextracted with EtOAc and concentrated. The residue was dissolved in Et₂Oand extracted with H₂O. The organic phase was separated, dried overMgSO₄ and concentrated. The residue was purified by chromatography onsilica (EtOAc/Cyclohexane) to afford the title compound (4.0 g; 31%;MH⁺=245).

Step D

The title compound from Step C above (5.4 g) was dissolved in CHCl₃ (5ml) and MeOH (30 ml) and treated with NaBH₄ (1.4 g). The mixture wasstirred at rt for 1 h and concentrated. The residue was suspended inCHCl₃ (50 ml) and extracted with aqueous HCl (50 ml; pH=1). The organicphase was separated, concentrated, then resuspended in toluene andconcentrated again. The residue was dissolved in toluene (50 ml). SOCl₂(3.94 ml) was added at 0° C. The reaction was stirred overnight at RT.The solvent was removed and the remaining material was suspended intoluene and concentrated. The residue was dissolved in CH₃CN (50 ml) andtreated with AgCN (2.96 g). The mixture was heated at reflux for 2 h andthen stirred at 60° C. overnight. The mixture was filtered and thefiltrate concentrated. The residue was purified by chromatography onsilica (EtOAc/Cyclohexane) to afford the title compound (4.4 g; 78%).

¹H-NMR δ CDCl₃ 3.1-3.2 (m, 4H), 5.3 (s, 1H), 6.7-6.9 (m, 3H), 7.0-7.2(m, 2H), 7.4 (m, 1H)

Step E

The title compound from Step D above (1.5 g) was dissolved in THF (5 ml)and slowly added at rt to a suspension of NaH (212 mg) in THF (10 ml).The mixture was heated at 60° C. for 30 min, then cooled to 0° C. andtreated with 1,2-dibromoethane (2.3 ml). The reaction was stirred at 60°C. for 3 h, cooled to rt and filtered. The filtrate was concentrated toafford the title compound (2.1 g; 99%).

¹H-NMR δ CDCl₃ 2.8-3.0 (m, 4H), 3.0-3.2 (m, 2H), 3.2-3.4 (m, 2H),6.8-7.2 (m, 4H), 7.6 (m, 1H), 7.8-7.9 (m, 1H)

Step F

The title compound from Step E above (2.1 g) and potassium phthalimide(5.4 g) were suspended in DMF (30 ml) and stirred at 60° C. overnight.The solvent was removed and the residue dissolved in CHCl₃, filtratedand concentrated. The residue was purified by chromatography on silica(EtOAc/cyclohexane) to afford the title compound (1.91 g; 76%)

¹HNMR δ CDCl₃ 2.8-3.2 (m, 4H), 3.4-3.6 (m, 2H), 3.7-3.9 (m, 2H), 6.8-7.0(m, 3H), 7.1-7.2 (m, 1H), 7.7-8.0 (m, 6H)

Step G

The title compound from Step F (1.90 g) was dissolved in toluene (20 ml)and treated with dibutyltin oxide (553 mg) and trimethylsilylazide (3.7ml). The mixture was heated under a N₂ atmosphere at 90° C. for 4 d. Thereaction was quenched with aqueous 1 N HCl (20 ml) and stirred for 1 hat 50° C. The phases were separated, the aqueous phase was extractedwith toluene and the combined organic phase concentrated. The residuewas purified by chromatography on silica (EtOAc/cyclohexane) to affordthe title compound (600 mg, 33%, MH⁺=472).

Step H

The title compound from Step G above (300 mg) was dissolved in ethanol(5 ml) and treated with hydrazine hydrate (127 mg). The solution wasstirred at 80° C. for 2 h and subsequently stirred for 1 h at rt. Thesolvent was removed and the residue treated with 1 N HCl (20 ml) andCHCl₃ (10 ml). The aqueous phase was separated, filtered andconcentrated affording the title compound (240 mg, 100% MH⁺=342).

Preparative Example 52

Step A

Commercially available 2,4-dichlorotoluene (24.6 g) and dry copper(I)cyanide (50 g) in N-methylpyrrolidone (130 ml) were heated under reflux(200-216° C.) for 4 d. While hot (110° C.), the mixture was poured intoa flask containing 33% aq. NH₄OH solution (390 ml) and toluene (100 ml)and stirred to break up the lumps. After the mixture was cooled to rt,Et₂O (100 ml) was added and filtered through cloth. The precipitate waswashed (2×100 ml Et₂O/CHCl₃ 1:1). The dark filtrate was poured into aseparatory funnel and the phases were separated with the aid ofadditional Et₂O (100 ml). The aqueous phase was extracted withEt₂O/CHCl₃ 1:1 (2×100 ml). The combined organic phases were washed with10% NH₄OH solution (4×110 ml, until the basic phase was no longer blue),with H₂O (100 ml), and brine (100 ml). The organic phase was separated,dried over MgSO₄ and concentrated. The residue was mixed with NaOH (24.8g) and diethylene glycol (275 ml) was added together with a few drops ofH₂O. The mixture was heated at 215-220° C. overnight. The cooled mixturewas diluted with H₂O (220 ml) and acidified to pH 1 with 10% aq. HCl.The suspension was filtered and the precipitate washed with 0.1 N HCl(50 ml). The solid was crystallised from glacial acetic acid to affordthe title compound (18.4 g, 78%; MH⁺=181).

Step B

Following a similar procedure as that described in Preparative Example49 Step B, the title compound from Step A above (22.1 g) was reacted toafford the title compound (30.0 g, 100%).

¹H-NMR (CDCl₃) δ: 2.65 (s, 3H), 3.91 (s, 3H), 3.92 (s, 3H), 7.32 (d,1H), 8.04 (dd, 1H), 8.56 (d, 1H).

Step C

Following a similar procedure as that described in Preparative Example49 Step C, the title compound from Step B above (30.0 g) was reacted.Differing from the cited example, the final mixture was allowed to standover the weekend to form the precipitate. After filtration, the crudetitle compound was obtained (38.0 g, 100%; [M-Br]⁺=469).

Step D

Following a similar procedure as that described in Preparative Example49 Step D, the title compound from Step C above (38.0 g) was reacted.Differing from the cited example, the hydrogenation was run for 2 days.(29.2 g, 77%; MH⁺=289).

Step E

Following a similar procedure as that described in Preparative Example49 Step E, the title compound from Step D above (4.32 g) was reacted andthe title compound obtained (1.77 g, 41%; MH⁺=285).

Step F

Following a similar procedure as that described in Preparative Example49 Step F, the title compound from Step E above (2.39 g) was reacted andthe title compound obtained (2.45 g, 100%; MNa⁺=309).

Step G

Following a similar procedure as that described in Preparative Example49 Step G, the title compound from Step F above (3.07 g) was reacted andthe title compound was obtained (2.17 g, 69%; MH⁺=296).

Step H

The title compound from Step G above (2.17 g) was dissolved in THF (30ml) and added to a suspension of NaH (250 mg) in THF (9 ml). The mixturewas heated at 90° C. for 1 h 15 min and cooled to rt. The mixture wasthen treated with 1,2-dibromoethane (1.6 ml) in THF (3.7 ml) and themixture was heated at 90° C. for 4 h 30 min. The mixture was cooled tort, diluted with 200 ml EtOAc, 20 ml brine and 20 ml sat. NH₄Cl. Theorganic phase was separated, dried over MgSO₄ and the residue purifiedby chromatography on silica (CH₂Cl₂) to afford the bromoethylintermediate (1.42 g, 50%; [MNH₄]⁺=419) and starting material (636 mg,24%). The bromoethyl compound (1.42 g) was dissolved in anhydrous DMF(18 ml) and treated with potassium phthalimide (1.96 g). The suspensionwas stirred at 80° C. overnight. The solvent was removed and the residuepartitioned between EtOAc (50 ml), H₂O (50 ml) and brine (50 ml). Theaqueous phase was extracted with EtOAc (2×50 ml) and the combinedorganic phase dried over MgSO₄ and concentrated. The residue waspurified by chromatography on silica (CH₂Cl₂/MeOH) to afford the titlecompound (1525 mg; 92%; MH⁺=469).

Step I

The title compound from Step H above (1475 mg) was dissolved inanhydrous toluene (25 ml) and treated with dibutyltin oxide (784 mg) andtrimethylsilylazide (8.3 ml). The mixture was heated under a N₂atmosphere at 90° C. for 3 days. The solvent was removed, the residuedissolved in MeOH (10 ml) and concentrated. The residue was partitionedbetween EtOAc (100 ml) and 10%. NaHCO₃ (100 ml). The aqueous phase wasextracted with EtOAc (2×70 ml) and the combined organic phase dried overMgSO₄ and concentrated. The residue was purified by chromatography onsilica (CH₂Cl₂/MeOH) to afford the title compound (1216 mg, 75%,MH⁺=512).

Step J

The title compound from Step I above (1216 mg) was dissolved inanhydrous MeOH (14 ml) and Et₃N (0.66 ml). The mixture was cooled to 5°C. and N,N′-dimethylamino-propylamine (0.71 ml) added. The mixture wasstirred at rt for 25 h and subsequently evaporated, toluene (10 ml)added, evaporated again and dried in HV. The residue was dissolved indioxane (8 ml) and H₂O (8 ml). To the slightly turbid solution was addedBoc₂O (2.6 g) and Et₃N (1.2 ml) and the mixture was stirred at rtovernight. After evaporation of the solvent, H₂O (20 ml) was added andthe solution acidified to pH˜4.0 by adding 1 M HCl and the aqueoussolution extracted with EtOAc (3×50 ml). The combined organic phase waswashed with brine (15 ml), separated, dried over MgSO₄ and concentrated.The residue was purified by chromatography on silica (CH₂Cl₂/MeOH) toafford the title compound (567 mg, 50%, MNa⁺=504).

Preparative Example 53

Step A

The title compound from Preparative Example 52 (215 mg) was dissolved inTHF (4 ml) and 33% NH₄OH solution (40 ml) was added. The solution wasstirred in a closed vessel at 80° C. overnight. The reaction mixture wasallowed to cool to rt and subsequently evaporated to dryness. The crudeproduct, which consisted of a mixture of the amide (MNa⁺=489) and thefree acid (MNa⁺=490), was dissolved in anhydrous THF (8.5 ml) andtriethylamine (0.28 ml) added. The ensuing precipitate was dissolved byadding anhydrous CH₃CN (6 ml). The mixture was cooled to −40° C. andethylchloroformate (0.17 ml) was slowly added. The mixture was stirredat −25° C. for 1 h and allowed to warm to 0° C. At 0° C. 7 MNH₃/MeOH-solution (10 ml) was added and the mixture was stirred at 0° C.for 30 min and for 1 h at rt. The mixture was concentrated and theresidue dissolved in H₂O (14 ml) and THF (3 ml). The pH was adjusted topH˜4.0 by adding 0.1 N HCl and the aqueous phase—after addition of brine(10 ml)—extracted with EtOAc containing 10% THF (4×33 ml) and CH₂Cl₂containing 10% THF (1×25 ml)). The combined organic phase was washedwith brine (15 ml), dried over MgSO₄ and concentrated to afford thetitle compound (241 mg; 100%, MNa⁺=489).

Step B

The title compound from Step A above (240 mg) was suspended/dissolved inCH₂Cl₂/MeOH 4:1 (5 ml) and a 4 M solution of HCl in dioxane (7 ml) addedafter which a clear solution was obtained. The mixture was stirred at rtfor 3 h and concentrated. The residue was partitioned between EtOAccontaining 10% THF (25 ml) and 0.01 N HCl (25 ml). The organic phase wasextracted with H₂O (25 ml) and 0.01 N HCl (25 ml). The combined aqueousphase was concentrated to afford the title compound (162 mg, 90%,MH⁺=367).

Preparative Example 54

Step A

The title compound from Preparative Example 49 Step C (47.6 g) wassuspended in CH₃CN (350 ml) and commercially available3-bromobenzaldehyde (13.9 ml) added. After the addition of DBN (24 ml),the mixture was heated at 100° C. for 1 h. The mixture was cooled andthe precipitate collected by filtration to afford the trans-olefin (7.5g). The mother liquor was concentrated to half its volume and pouredinto H₂O (300 ml). The mixture was extracted with EtOAc (2×300 ml), theorganic phase washed with 5% HCl (2×80 ml), dried over MgSO₄ andconcentrated. To this residue was added the trans olefin from above andthe mixture was suspended in H₂O (500 ml), MeOH (60 ml) and dioxane (60ml). After the addition of KOH (47 g), the mixture was heated at 60° C.for 16 h, cooled to rt and washed with CH₂Cl₂ (3×100 ml). The aqueousphase was made acidic (pH˜1) by adding conc. HCl, filtered, theprecipitate washed with H₂O (150 ml) and air-dried to afford the titlecompound as a mixture of cis/trans-olefins (26.5 g; 88%; MH⁺=347).

Step B

The title compound from Step A above (6 g) was dissolved in MeOH (450ml) and EtOAc (150 ml). After the addition of a suspension of 5% Pt/C(2.5 g) in 10% HCl (5 ml) and MeOH (10 ml), the mixture was hydrogenatedfor 6 h. The mixture was filtered, the catalyst washed with MeOH (60 ml)and the filtrates evaporated to afford the title compound (5.5 g, 91%).

¹HNMR δ (DMSO-d₆) δ 2.81-2.90 (m, 2H), 3.13-3.27 (m, 2H), 7.23-7.32 (m,2H), 7.39-7.45 (m, 1H), 7.51 (s, 1H), 7.85-7.95 (m, 3H)

Step C

The title compound from Step B above (4 g) was suspended in sulfolane (9ml) and treated with polyphosphoric acid (30 g). The mixture was heatedunder N₂ at 175-180° C. for 2 h 30 min and poured into ice-water (250ml). The mixture was stirred at rt overnight and the precipitatecollected by filtration to afford the crude title compound (3.56 g; 94%;MH⁺=331).

Step D

The title compound from Step C above (3.5 g) was dissolved in N-methylpyrrolidone (25 ml) and CuCN (900 mg) added. The mixture was heated at200° C. for 8 h, cooled to rt and diluted with H₂O (200 ml) and 1 M HCl(50 ml). The mixture was extracted with EtOAc (3×100 ml) and thecombined organic phase washed with H₂O (100 ml) and brine (100 ml). Theorganic phase was dried over MgSO₄ and evaporated. The residue wasdissolved in dioxane (50 ml) and conc. HCl (50 ml) added. The mixturewas heated at 90° C. for 18 h and the solvents evaporated. The residuewas suspended in MeOH (75 ml), treated with SOCl₂ (1.5 ml) and heatedunder reflux for 1 h 30 min. The mixture was concentrated to half itsvolume, diluted with Et₂O (300 ml) and washed with sat. NaHCO₃ (80 ml)and brine (80 ml). The organic phase was separated, dried over MgSO₄ andevaporated. The residue was purified by chromatography on silica(EtOAc/hexane, 1:4) to afford the title compound (1040 mg; 27%;MH⁺=325).

Step E

The title compound from Step D above (1040 mg) was dissolved in CHCl₃(15 ml) and MeOH (15 ml) and the NaBH₄ (150 mg) added. The mixture wasstirred at rt for 1 h, diluted with ice water (80 ml) and extracted withEtOAc (2×100 ml). The organic phase was dried over MgSO₄ andconcentrated. The residue was purified by chromatography on silica(CH₂Cl₂/acetone, 98:2->CH₂Cl₂/acetone, 95:5) to afford the titlecompound (817 mg, 78%, MNa⁺=349).

Step F

The title compound from Step E above (817 mg) was dissolved in THF (10ml) and treated with SOCl₂ (0.46 ml). The mixture was stirred at rtovernight and the solvents evaporated. The residue was dissolved inCH₃CN (10 ml) and benzene (5 ml) and added to a suspension of AgCN (406mg) in CH₃CN (10 ml). The mixture was heated at 90° C. for 5 h, filteredand the salts washed with CH₃CN (10 ml). The filtrates were evaporatedand the residue purified by chromatography on silica (CH₂Cl₂/acetone,98:2) to afford the title compound (572 mg, 68%, MH⁺=336).

Step G

The title compound from Step F above (676 mg) was suspended in THF (20ml) and DMF (5 ml) and treated under a N₂ atmosphere with NaH (106 mg).The mixture was heated at ˜95° C. for 75 Min, cooled to rt and treatedwith a solution of 1,2-dibromoethane (0.7 ml) in THF (3 ml). The mixturewas then heated at 95° C. for 10 h, cooled to rt and treated with sat.NH₄Cl (15 ml) and EtOAc (100 ml). The organic phase was separated,washed with brine (15 ml), dried over MgSO₄ and concentrated. Theresidue was dissolved in DMA (8 ml) and treated with potassiumphthalimide (554 mg). The mixture was heated at 60° C. overnight, thesolvent removed and the residue dissolved in EtOAc (50 ml) and H₂O (15ml). The organic phase was separated, washed with brine (15 ml) andconcentrated. The residue was purified by chromatography on silica(CH₂Cl₂/acetone, 98:2) to afford the title compound (740 mg, 72%, MNH₄⁺=526).

Step H

The title compound from Step G above (600 mg) was suspended in toluene(5 ml) and treated with dibutyltin oxide (138 mg) andtrimethylsilylazide (1.45 ml). The mixture was heated under a N₂atmosphere at 90-95° C. for 3 d and the solvent evaporated. The residuewas suspended in MeOH (10 ml) and the solvent evaporated. The residuewas dissolved in EtOAc (30 ml) water (10 ml). The organic phase wasseparated, dried over MgSO₄ and concentrated. The residue was purifiedby chromatography on silica (CH₂Cl₂/MeOH, 95:5) to afford the titlecompound (415 mg, 68%, MH⁺=552).

Step I

The title compound from Step H above (415 mg) was dissolved in MeOH (6ml) and triethylamine (0.23 ml). The mixture was cooled to 0° C. and3-dimethylaminopropylamine (0.23 ml) added. The mixture was stirred at0° C. for 10 min and at rt overnight. The mixture was concentrated,dissolved in MeOH (10 ml), again concentrated and dried in HV. Theresidue was dissolved in dioxane (5 ml) and H₂O (5 ml) and the pHadjusted to pH=8-9 by adding 1 M KOH. The mixture was then treated withBoc2O (870 mg) and stirred overnight. The mixture was adjusted to pH=4by adding 1 M HCl and diluted with EtOAc (150 ml). The organic phase wasseparated and the aqueous phase extracted with EtOAc (2×75 ml). Thecombined organic phase was dried over MgSO₄ and concentrated. Theresidue was purified by chromatography on silica gel (CH₂Cl₂/MeOH,95:5->4:1) to afford the title compound (227 mg, 58%, MH⁺=522).

Step J

The title compound from Step I above (227 mg) was dissolved in dioxane(10 ml) and 1 M KOH (3.75 ml) added. The mixture was stirred at rtovernight and the pH adjusted to pH=4 by adding 1 M HCl. The mixture wasextracted with EtOAc, containing 10% THF (2×150 ml). The organic phasewas separated, dried over MgSO₄ and concentrated to afford the titlecompound (177 mg, 82%; MH⁺=494).

Preparative Example 55

If one were to follow a similar procedure as described in PreparativeExample 54, but using 3-fluorobenzaldehyde in Step A and omitting StepD, one would obtain the desired compound.

Preparative Example 56

Step A

The title compound from Preparative Example 54 (177 mg) was dissolved inTHF (6 ml) and triethylamine (0.2 ml) added. The precipitate wasdissolved/suspended by adding CH₃CN (3 ml). The mixture was cooled to−40° C. and ethylchloroformate (0.1 ml) was slowly added. The mixturewas stirred at −25° C. for 1 h and allowed to warm to 0° C. At 0° C. 7 MNH₃/MeOH-solution (7 ml) was added and the mixture was stirred at 0° C.for 30 min and 1 h at rt. The mixture was concentrated and the residuedissolved in H₂O (10 ml) and THF (2 ml). The pH was adjusted to pH˜4.0by adding 100 mM HCl and the aqueous phase extracted with EtOAc (4×30ml) containing 10% THF. The organic phase was dried over MgSO₄ andconcentrated to afford the title compound (110 mg; 62%, MNa⁺=514).

Step B

The title compound from Step A above (103 mg) was dissolved in THF (2ml) and a 4 M solution of HCl in dioxane (5 ml) added. The mixture wasstirred at rt for 2 h and concentrated. The residue was dissolved in H₂O(20 ml) and washed with EtOAc (2×8 ml). The aqueous phase wasconcentrated, the residue dissolved in 50 mM HCl (6 ml) and filteredthrough a Millex VV (0.1 μM) filter unit. The filtrate was concentratedto afford the title compound (90 mg, 94%, MH⁺=392).

Preparative Example 57

If one were to follow a similar procedure as described in PreparativeExample 56, but using the title compound from Preparative Example 55,one would obtain the desired compound.

Preparative Example 58

Step A

A suspension of NaH (66 mg) in THF (10 ml) was added to a solution ofthe title compound from Preparative Example 13 Step A (0.57 g) in THF(20 ml) and heated at 65° C. for 1 h. Then the mixture was cooled to 0°C. and a solution of Preparative Example 21 (0.74 g) in THF (10 ml) wasadded. The suspension was heated at 65° C. for 5 h and then diluted withethyl acetate. The organic phase was washed with water, brine and driedover MgSO₄. Removal of the solvents and column chromatography(EtOAc/hexane, 1:4) afford the title compound (630 mg, 58%, MH⁺=421).

Step B

The title compound from Step A above (632 mg) was dissolved in DMF (10ml) and treated with NaN₃ (1.2 g) and NH₄Cl (963 mg). The mixture washeated under a N₂ atmosphere at 110° C. for 3 d and the solventevaporated. Column chromatography (CH₂Cl₂/MeOH, 9:1) afford the titlecompound (350 mg, 51%, MH⁺=464).

Step C

The title compound from Step B above (350 mg) was dissolved in THF (10ml) and treated with TBAF.3H₂O. The mixture was stirred at rt for 4 hand the solvent evaporated. Preparative TLC using CH₂Cl₂/MeOH (4:1)afford the title compound (121 mg, 50%, MH⁺=320).

Preparative Example 59

Step A

Commercially available 2-Brom-5-chlor-toluene (123 g) was diluted withEt₂O (70 ml) and 10% of this solution was added to a mixture of Mg (15.2g) and iodine (3 crystals) in Et₂O (250 ml). After the Grignard reactionhad started, the remaining starting material was added at such a rate tomaintain gentle reflux. After the complete addition of the startingmaterial, the mixture was heated at 60° C. oil-bath temperature for 45Min. The mixture was then cooled to rt and poured onto a mixture ofdry-ice in Et₂O (1800 ml). The mixture was allowed to warm to rt over aperiod of 2 h and the solvent removed. The residue was dissolved withEtOAc (1200 ml) and washed with 3 N HCl (3×1000 ml). The organic phasewas separated, dried over MgSO₄, filtered and concentrated to afford thetitle compound (94.3 g, 92%)

¹HNMR δ (DMSO-d₆) 2.51 (s, 3H), 7.33 (dd, 1H), 7.39 (d, 1H), 7.81 (d,1H), 12.9 (br-s, 1H)

Step B

The title compound from Step A above (47 g) was dissolved in THF (500ml) and the mixture cooled to −60° C. At −60° C. a 1.3 M solution ofsec-BuLi (455 ml) in hexane was slowly added as to keep the internaltemperature below −30° C. The precipitate began to dissolve after theaddition of more than half of the sec-BuLi solution. After the completeaddition of sec-BuLi, the deep red solution was stirred at −50° C. for 1h. The anion solution was then transferred via canula to a cooled (−40°C.) solution of commercially available 3-chlor-benzylbromide (62.3 g) inTHF (150 ml). The addition of the anion was at such a rate as tomaintain −40° C. during the addition. After the addition of the anionwas completed, the mixture was stirred at −40° C. for 1 h and was thenallowed to warm to rt over a period of 3 h. The reaction was quenched byadding 2 M NaOH (1000 ml) and the THF removed in vacuo. The remainingsolution was extracted with cyclohexane (2×500 ml) and the aqueuousphase acidified to PH=1 by adding conc. HCl. The mixture was extractedwith EtOAc (3×400 ml), the organic phase dried over MgSO₄, filtered andconcentrated to afford the title compound (71 g, 87%).

¹HNMR δ (acetone-d₆) 2.83-2.91 (m, 2H), 3.22-3.31 (m, 2H), 7.13-7.40 (m,6H), 7.98 (d, 1H).

Step C

The title compound from Step B above (71 g) was suspended in sulfolane(250 ml) and PPA (700 g) added. The mixture was stirred with amechanical stirrer and heated at 170° C. oil-bath temperature for 9 h.The hot mixture (˜120° C.) was then poured onto crushed-ice (4000 g) andstirred overnight. The precipitate was allowed to settle for 30 Min andthe aqueous phase decanted. The residue was dissolved in Et₂O (1500 ml)and washed with 1 M NaOH (2×500 ml). The organic phase was dried overMgSO₄, filtered and concentrated to afford the title compound (50 g,75%).

¹HNMR δ (CDCl₃) 3.16 (s, 4H), 7.23 (d, 2H), 7.32 (dd, 2H), 8.0 (d, 2H)

Step D

The title compound from Step C above (25 g) was dissolved in toluene(160 ml) and added to a mixture of KCN (11.7 g), dipiperidinomethane(7.26 ml), sulfolane (2 ml) and 1,4-Bis-(diphenylphosphino)-butane (6g). The mixture was degassed by sonication under a stream of nitrogenand then palladium(II)-acetate (1.6 g) was added. The mixture was thenheated in a sealed glass reaction vessel at 160° C. oil-bath temperaturefor 18 h. The mixture was cooled to rt, diluted with CH₂Cl₂ (800 ml) andwashed with H₂O (300 ml) and brine (300 ml). The organic phase wasseparated, dried over MgSO₄, filtered and concentrated. The residue wasdiluted with EtOAc (90 ml) and sonicated. The suspension was thentreated with cyclohexane (400 ml) and allowed to stand for 30 Min. Theprecipitate was collected by filtration and air-dried to afford thetitle compound (18 g, 77%, MH⁺=259).

Step E

The title compound from Step D above (18 g) was suspended in EtOH (75ml) and H₂O (20 ml) and the KOH (19.3 g) added. The mixture was heatedat 100° C. oil-bath temperature for 12 h, concentrated and the residuedissolved in H₂O (500 ml). The aqueous phase was acidified to pH=1 byadding conc. HCl and the precipitate collected by filtration andair-dried to afford the title compound (19.5 g, 95%, MH⁺=297).

Step F

The title compound from Step E above (19.5 g) was suspended in MeOH (600ml) and treated with thionyl chloride (29 ml). The mixture was thenheated at 90° C. oil-bath temperature for 3 h, the hot mixture filteredand concentrated. The residue was dissolved in CH₂Cl₂ (800 l) and washedwith sat. NaHCO₃ (200 ml). The organic phase was separated, dried overMgSO₄, filtered and concentrated to afford the title compound (18.8 g,88%, MH⁺=325).

Step G

The title compound from Step F above (18.8 g) was dissolved in CHCl₃(250 ml) and MeOH (250 ml). The mixture was then treated with NaBH₄(2.47 g) in small portions. After the complete addition of the reducingagent, the mixture was stirred at rt for 1 h. The mixture was pouredinto ice-water (800 ml), the organic phase separated and the aqueousphase extracted with EtOAc (300 ml). The combined organic phase wasdried over MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica (CH₂Cl₂ to CH₂Cl₂/acetone, 98:2 toCH₂Cl₂/acetone, 95:5) to afford the title compound (11.9 g, 63%,MNa⁺=349).

Step H

The title compound from Step G above (11.9 g) was dissolved in THF (150ml) and the mixture cooled to 0° C. At 0° C. thionyl chloride (6.5 ml)was added and the mixture was allowed to warm to rt overnight. Thesolvent was then removed in vacuo to afford the crude title compound.

¹HNMR δ (CDCl₃) 2.93-3.05 (m, 2H), 3.70-3.80 (m, 2H), 3.90 (s, 6H), 6.10(s, 1H), 7.40 (d, 2H), 7.78-7.86 (m, 4H).

Step I

The title compound from Step H above was dissolved in CH₃CN (300 ml) andbenzene (95 ml). After the addition of AgCN (5.9 g) the mixture washeated at 95° C. oil-bath temperature for 2 h 45 Min. The mixture wasfiltered while hot and the salts washed with CH₂Cl₂ (100 ml). Thefiltrate was concentrated and the residue purified by chromatography onsilica (CH₂Cl₂/acetone, 98:2) to afford the title compound (11.3 g, 92%,MH⁺=336).

Preparative Example 60

Step A

The title compound from Preparative Example 59 Step C (9.5 g) wasdissolved in CHCl₃ (100 ml) and MeOH (60 ml) at 0° C. The mixture wasthen treated with NaBH₄ (1.64 g) in small portions. After the completeaddition of the reducing agent, the mixture was stirred at rt for 3 h.Water (50 ml) was added and the mixture was concentrated to half of itsvolume and extracted with EtOAc (2×150 ml). The combined organic layerswere washed with water (50 ml), brine (50 ml), dried over MgSO₄ andconcentrated. The crude product was used without further purification (9g, 90%, MNa⁺=301).

Step B

The crude title compound from Step A above (9 g) was dissolved in THF(100 ml) and the mixture was cooled to 0° C. At 0° C. thionyl chloride(7.1 ml) was added and the mixture was allowed to warm to rt overnight.The solvent was then removed in vacuo to afford the title compound (9.2g).

Step C

The title compound from Step B above (9.2 g) was dissolved in CH₃CN (180ml) and benzene (60 ml). After the addition of solid AgCN (5.2 g) themixture was heated at 90° C. oil-bath temperature for 2.5 h. The mixturewas filtered while hot through celite and the salts washed with CH₂Cl₂(200 ml). The filtrate was concentrated to give the crude title compound(8.66 g, 93%, MH⁺=288).

Preparative Example 61

Step A

The title compound from Preparative Example 59 (3.8 g) was suspended inTHF (50 ml) and DMF (35 ml). The mixture was treated under a N₂atmosphere with NaH (408 mg) and the mixture was heated at 95° C.oil-bath temperature for 90 Min, cooled to rt and treated with the titlecompound from Preparative Example 21 (4.78 g). The mixture was thenheated at 90-95° C. for 4 h, cooled to rt and quenched with sat. NH₄Cl(75 ml) and brine (90 ml). The organic phase was separated and theaqueous layer extracted with EtOAc (2×50 ml). The combined organic phasewas dried over MgSO₄ and concentrated. The residue was purified bychromatography on silica (CH₂Cl₂/MeOH, 95:5) to afford the titlecompound (5 g, 82%, MH⁺=537).

Step B

The title compound from Step A above (5 g) was dissolved in DMA (90 ml)and treated with NaN₃ (5.9 g) and NH₄Cl (4.8 g). The mixture was heatedunder a N₂ atmosphere at 100-105° C. for 50 h. The cooled mixtureconcentrated and the residue dissolved in EtOAc (600 ml) and H₂O (200ml). The aqueous layer was acidified to pH=4 by adding 1 M HCl and theorganic phase separated. The aqueous phase was extracted with EtOAc(2×80 ml) and the combined organic extracts washed with 100 mM HCl (200ml) and brine (200 ml). The organic phase was separated, dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography on silica (CH₂Cl₂/MeOH 9:1->4:1) to afford the titlecompound (4 g, 74%, MH⁺=580).

Step C

The title compound from Step B above (4 g) was dissolved in dioxane (153ml). After the addition of 1 M KOH (42.5 ml), the mixture was stirred atrt overnight. The mixture was concentrated and then 43 ml 1 M HCl added.The precipitate was dissolved in EtOAc (100 ml) and H₂O (100 ml) and theorganic phase separated. The aqueous phase was extracted with EtOAc (100ml) and the organic phase combined. The solvent was then removed toafford the title compound (3.9 g, quanta, MH⁺=552).

Preparative Example 62-64

Following a similar procedure as that described in Preparative Example61 but using the sulfamidates and compounds from the PreparativeExamples as indicated in the Table below, the title compounds wereobtained.

Preparative Preparative Example Example Sulfamidate Title compound MH⁺62 59

538 63 59

566 64 60

475

Preparative Example 65

If one were to treat the title compound from Preparative Example 59according to the procedures described in Preparative Example 61, butusing the sulfamidate as indicated in the table below, one would obtainthe title compound.

Preparative Preparative Example Example Sulfamidate Title compound 65 59

Preparative Example 66

Step A

The title compound from Preparative Example 61 Step A (1000 mg) wassuspended in MeOH (10 ml) and hydroxylamine hydrochloride (517 mg) and a5.5 M solution of sodium methoxide in MeOH (1.4 ml) added. The mixturewas heated in a pressure bottle at 110° C. for 12 h and then the solventremoved. The residue was purified by chromatography on silica(cyclohexane/EtOAc 1:3->1:1) to afford the title compound (210 mg, 20%,MH⁺=570).

Step B

The title compound from Step A above (180 mg) was dissolved in MeOH (10ml) and sodium methoxide (233 mg) and diethyl carbonate (1130 mg) added.The mixture was heated at 110° C. in a pressure bottle overnight. Thesolvent was removed and the residue purified by chromatography on silica(CHCl₃) to afford the title compound (110 mg, 58%, M⁺−27=568).

Step C

The title compound from Step B above (110 mg) was dissolved in THF (25ml) and treated with 1M KOH (6 ml). After stirring at rt overnight, 1MHCl (2.8 ml) was added and the solvents removed to afford the crudetitle compound (105 mg, quant., M⁺−27=540).

Preparative Example 67

Step A

Hydroxylamine hydrochloride (401 mg) was suspended in anhydrous MeOH (14ml) and a 5.5 M solution of sodium methoxide in MeOH (0.946 ml) added.This mixture was stirred at rt for 45 min and the title compound fromPreparative Example 61 Step A (1400 mg) was added. The resulting mixturewas heated in a closed vessel at 100° C. overnight and subsequentlyallowed to cool down to rt. Due to incomplete conversion, hydroxylaminehydrochloride (401 mg) and a 5.5 M solution of sodium methoxide in MeOH(0.946 ml) were added and the mixture was heated again at 100° C. for 20h. After cooling down to rt, the salts were filtered off and washed withEtOAc (15 ml) and CHCl₃ (15 ml). The united organic phases wereevaporated and the residue purified by chromatography on silica(cyclohexane/EtOAc 8:2->6:4) to afford the title compound fromPreparative Example 66 Step A (300 mg, 20%, MH⁺=570) and the titlecompound (1130 g, 74%, MNa⁺=577).

Step B

The title compound from Step A above (1380 g) was dissolved in THF (30ml) and treated with 1M KOH (9 ml). After stirring at rt overnight, 1MKOH (9 ml) was added and stirring continued for 22 h. The reactionmixture was acidified with 4 M HCl to pH 2-3, extracted with EtOAc/THF10/1 (4×40 ml) and the combined organic extracts washed with brine (20ml). The organic phase was separated, dried over MgSO₄, filtered andconcentrated to afford the title compound (1220 mg, quant., M⁺−27=499,MNa⁺=549).

Preparative Example 68

Step A

The N-hydroxyamidine product from Preparative Example 66 Step A (300 mg)was dissolved in anhydrous dichloromethane (5 ml), the solution cooleddown to 0° C. and triethylamine (147 μl) and trifluoroacetic anhydride(103 μl) added. The reaction mixture was stirred at rt overnight. Due toincomplete conversion, triethylamine (221 μl) and trifluoroaceticanhydride (155 μl) were added at 0° C. and stirring was continued at rtfor 3 d. Dichloromethane (9 ml) and water (10 ml) were added to thestirred mixture. After 5 min, the separated organic phase was washedwith brine (5 ml), dried over MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica (cyclohexane/EtOAc8:2->7:3) to afford the title compounds A (267 mg, 68%, MNa⁺=766) and B(36 mg, 10%, MNa⁺=670).

Step B

The title compounds A (267 mg; MNa⁺=766) and B (36 mg, MNa⁺=670) fromStep A above were dissolved in dioxane (11 ml) and water added (11 ml).The resulting suspension was treated with 1M NaOH (3.6 ml). Afterstirring at rt overnight, the reaction mixture was acidified with 1M HClto pH 2-3, extracted with EtOAc (4×40 ml) and the combined organicphases dried over MgSO₄, filtered and concentrated to afford the titlecompound (282 mg, quant., MNa⁺=642).

Preparative Example 69

Step A

To the title compound of Preparative Example 61 Step A (500 mg) inanhydrous DMF (10 ml) was added K₂CO₃ (123 mg). After cooling down to 0°C., methyl iodide (75 μl) was added dropwise to the stirred mixture.After 10 min, the mixture was allowed to rt and stirred overnight. Thereaction mixture was cooled down to 0° C., diluted with acidifiedsaturated aq. NaCl solution (pH 2-3) and added to stirred EtOAc (150ml). The separated organic phase was washed with brine (2×25 ml), driedover MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica (cyclohexane/EtOAc 8:2->7:3) to afford thetitle compounds: the 1-Me-tetrazole (170 mg, 33%, MH⁺=580) and the2-Me-tetrazole (163 mg, 32%, MH⁺=580).

Step B

The title compounds from Step A above (170 mg of the 1-Me-tetrazole and163 mg of the 2-Me-tetrazole) were separately dissolved in dioxane (5.5ml) and treated with 1M KOH (1.5 ml) each. After stirring at rt for 3 h,the reaction mixtures were concentrated to ⅓ of their volumes and the pHadjusted to 3 with 1M HCl. The resulting aq. suspension was extractedwith EtOAc (3×25 ml) and the combined organic phases dried over MgSO₄,filtered and concentrated to afford the title compounds: the1-Me-tetrazole (171 mg, quant., M⁺−27=524) and the 2-Me-tetrazole (172mg, quant., M⁺−27=524).

Preparative Example 70

Step A

The title compound from Preparative Example 61 (2 g) was dissolved inTHF (75 ml) and CH₃CN (75 ml) and triethylamine (4 ml) added. Themixture was cooled to −40° C. and ethylchloroformate (2.3 ml) was slowlyadded. The mixture was stirred at −25° C. for 1 h, filtered and thesalts washed with 35 ml THF. The filtrate was placed in a cooling bath(−20° C.) and a 33%-solution of NH₄OH (30 ml) was added. The mixture wasstirred at −20° C. for 30 min and 15 min at rt. Since LC-MS indicatedthat the conversion was not complete, the mixture was concentrated. Thereaction was repeated using the same reaction conditions. After thesecond run LC-MS indicated that the reaction was completed. The mixturewas concentrated to afford the crude title compound together with saltsfrom the reaction (MNa⁺=572).

Step B

The crude title compound from Step A above was suspended in CHCl₃ (25ml) and the mixture cooled to 0° C. At 0° C. TFA (25 ml) was added andstirring at 0° C. was continued for 2 h. The mixture was concentratedand the residue dissolved in H₂O (15 ml). The pH was adjusted to pH=7.0by adding 10% NaOH and the neutral solution loaded onto a RP-column(Merck; silica gel 60 RP-18, 40-63 μM). The column was washed with H₂Oto remove the salts, followed by CH₃CN/H₂O (1:1) to elute the titlecompound (1.3 g, 88%, MH⁺=406).

Preparative Example 71-87

Treating the compounds from the Preparative Examples with the amines asindicated in the Table below, according to a modified procedure asdescribed in Preparative Example 70, the title compounds were obtainedas HCl-salts.

Modifications:

-   Step A The crude mixture from Step A was dissolved in H₂O and the pH    adjusted to pH=4.0 by adding 1 M HCl. The mixture was then extracted    with EtOAc, the organic phase separated, dried over MgSO₄, filtered    and the solvents removed.-   Step B The residue after removal of the Teoc protecting group was    diluted with 1M HCl and the aqueous phase washed with EtOAc.    Concentration of the aqueous phase afforded the title compound as    HCl-salt.

Preparative Preparative Example Example Amines Title compound MH⁺ 71 61

462 72 61

434 73 61

462 74 61

490 75 61

486 76 61

546 77 62

420 78 62

447 79 63 NH₃

420 80 66

478 81 67

437 82 68

530 83 69 1-Me-tetrazole

406 84 69 2-Me-tetrazole

406 85 61 Step B none

436 86 61 none

408 87 64 none

374

Preparative Example 88

Step A

Commercially available anthraquinone (8.0 g) was suspended in CHCl₃ (100ml) and conc. H₂SO₄ (20 ml) was added. The resulting biphasic system wasrapidly stirred and NaN₃ (3.1 g) was added in portions at rt. Themixture was stirred for 1 h at rt and at 30-40° C. (water bath) foranother 3 h. After the addition of ice water (80 ml), the precipitatewas collected by filtration and dried to afford the title compound (8.40g; 97%; MH⁺=224).

Step B

The title compound from Step A above (8.0 g) was dissolved in DMSO (140ml) under N₂ at 10° C. After the addition of KOtBu (5.7 g), the mixturewas stirred for 15 min at that temperature. After the addition of CH₃I(4.2 ml), the mixture was allowed to warm to rt and stirred for 2 h.After the addition of 1 M HCl (130 ml) and EtOAc (100 ml), the organicphase was separated and the aqueous phase extracted with EtOAc (2×50ml). The combined organic phase was washed with H₂O (50 ml), brine (50ml), dried over MgSO₄ and concentrated. The residue was purified bychromatography on silica (EtOAc/cyclohexane) to afford the titlecompound (4.88 g; 61%; MH⁺=238).

Step C

Tosylmethyl isocyanide was dissolved in DMSO (10 ml) under N₂ at 10° C.and KOtBu (1.36 g) was added. The mixture was stirred for 5 min and MeOH(0.173 ml) was added. The title compound from Step B above (0.8 g) wasimmediately added to the mixture. After 10 min dibromoethane (1.51 ml)was added and stirring was continued for 1 h at rt. The mixture wasdiluted with EtOAc (10 ml) and sat. NH₄Cl (30 ml) was added. The organicphase was separated and the aqueous phase was extracted with EtOAc (2×50ml). The combined organic phase was washed with H₂O (50 ml), brine (50ml), dried over MgSO₄ and concentrated. The residue was dissolved in DMF(40 ml) and potassium phthalimide (3.13 g) added. The resulting mixturewas heated to 60° C. for 3 h and concentrated. The residue was suspendedin CHCl₃ and filtered. The filtrate was concentrated and the residuepurified by chromatography on silica (EtOAc/cyclohexane) to afford thetitle compound (612 mg; 43%; MH⁺=422).

Step D

The title compound from Step C above (0.6 g) was dissolved in toluene(30 ml) under N₂ and dibutyltin oxide (1.68 g) and trimethylsilylazide(8.9 ml) were added. The mixture was then heated at 75° C. for 24 h. Themixture was concentrated, the residue suspended in EtOAc (40 ml) and 1 MHCl (40 ml) and stirred for 2 h at rt. MeOH (10 ml) was added and theorganic phase was separated. The aqueous phase was extracted with EtOAc(3×20 ml) and the combined organic phase was washed with brine (20 ml),dried over MgSO₄ and evaporated. The residue was purified bychromatography on silica (MeOH/CH₂Cl₂) to afford the title compound (565mg; 84%; MH⁺=465).

Step E

The title compound from Step D above (0.22 g) was dissolved in EtOH (7ml) and CHCl₃ (3 ml) and the mixture was heated to 80° C. Hydrazinemonohydrate (0.108 g) was added and the mixture was stirred at 80° C.for 1 h. The mixture was allowed to cool to rt within 1 h. Theprecipitate was removed by filtration and washed with EtOH. The filtratewas concentrated and dissolved in CHCl₃ (20 ml) and 1 M HCl (10 ml). Theaqueous phase was separated, filtered and evaporated to afford the titlecompound (85 mg; 48%; MH⁺=335).

Preparative Example 89

Step A

To a solution of the commercially available L-pyroglutamic acidethylester (15.7 g) in methylene chloride (90 ml) was sequentially addedat rt di-tert-butyldicarbonate (24 g) and a catalytic amount of DMAP(120 mg). After stirring for 6 h at rt the reaction mixture was quenchedwith saturated brine and extracted with methylene chloride. (3×30 ml).The organic phase was dried over MgSO₄, concentrated and the residuepurified by flash chromatography on silica (CH₂Cl₂) to afford the titlecompound (16.3 g, 63%, MNa⁺=280).

Step B

A solution of the title compound from Step A above (16.3 g) in toluene(100 ml) was cooled to −78° C. and triethylborohydride (67 ml of a 1.0 Msolution in THF) was added dropwise over 90 minutes. After 3 h, 2,6lutidine (43 ml) was added dropwise followed by DMAP(20 mg). To thismixture was added TFAA (11 ml) and the reaction was allowed to come toambient temperature over 2 h. The mixture was diluted with ethyl acetateand water and the organics were washed with 3 N HCl, water, aqueousbicarbonate and brine. The organic phase was dried over MgSO₄, filteredand concentrated. The residue was purified by chromatography on silica(cyclohexane/EtOAc 5:1) to afford the title compound (10.9 g, 72%,MNa⁺=264).

Step C

A solution of the title compound from Step B above (3.5 g) in 1,2dichloroethane (75 ml) was cooled to −15° C. and Et₂Zn (25 mL of a 1.0 Msolution in THF) was added dropwise. To this mixture was added drop wiseClCH₂I (4.5 ml) over 30 minutes. After stirring for 18 h at −15° C. themixture was quenched with saturated aqueous bicarbonate and the solventwas evaporated and the reaction was taken up in ethyl acetate and washedwith brine. The organic phase was dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica(cyclohexane/EtOAc 4:1) to afford the diastereomerically pure titlecompound (1.5 g, 41%, MNa⁺=278).

Step D

A solution of the title compound from Step C above (1.4 g) in MeOH (40ml) and THF (20 ml) was treated with 1 N LiOH (10 ml) and stirredovernight at rt. The reaction mixture was acidified to pH 4.5 with 2 NHCl and stirred for 15 min at rt. The mixture was then extracted withEtOAc, the organic phase washed with brine, dried over MgSO₄ andevaporated to afford the title compound (1.2 g, 96%, MNa⁺=250).

Step E

To a solution of the title compound from Step D above (1.2 g) in THF (20ml) was added at −15° C. 4-methylmorpholine (710 μl) and then isobutylchloroformate (780 μl) over 5 minutes and stirred then for 30 minutes.The reaction mixture was cooled to −30° C. and treated with a solutionof NH₃ in dioxane (25 ml, 0.5 M in dioxane). The reaction mixture wasstirred for 30 minutes, warmed to rt and stirred overnight. The reactionmixture was acidified to pH 4.5 with 10% aqueous citric acid andextracted with ether (3×50 ml). The organic phase was dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica (cyclohexane/EtOAc 1:10) to afford the title compound (1.0 g,84%, MNa⁺=248).

Step F

To a stirred solution o of the title compound from Step E above (0.9 g)in methylene chloride (5 ml) was sequentially added at 0° C. TFA (5 ml).After stirring for 12 h at 0° C. the reaction mixture was concentratedunder reduced pressure to afford the title compound (0.9 g, 100%,MH⁺=127).

Step G

The title compound from Step F above (450 mg) was dissolved in CH₂Cl₂(12 ml) and triethylamine (0.4 ml). The mixture was cooled to 0° C. andDMAP (25 mg) was added followed by fumarylchloride (0.099 ml). Themixture was stirred at 0° C. and allowed to warm to rt overnight. Themixture was concentrated to afford the crude title compound (MH⁺=333).

Step H

To a cooled (0° C.) solution of DMF (4 ml) was carefully addedoxalylchloride (0.32 ml). After the addition was completed, the mixturewas stirred at 0° C. for 5 min. Then pyridine (0.6 ml) was addedfollowed by a solution of the crude title compound from Step G above inDMF (2 ml) and CH₂Cl₂ (4 ml). The mixture was then stirred at 0° C. for2 h. The mixture was concentrated and the residue partitioned betweenEtOAc (50 ml) and brine (25 ml). The organic phase was separated and theaqueous phase extracted with EtOAc (2×25 ml). The combined organic phasewas dried over MgSO₄, filtered and concentrated. The residue waspurified by chromatography on silica (CH₂Cl₂/MeOH, 95:5) to afford thetitle compound (250 mg, 92%, MH⁺=297).

Step I

The title compound from Step H above (328 mg) was dissolved in CHCl₃ (3ml) and MeOH (3 ml). The mixture was then treated with ozone accordingto Preparative Example 2 Step C to afford the title compound (350 mg,80%, MH⁺=165 (aldehyde); MH⁺=219 (hemiacetal)).

Preparative Example 90

Step A

To a stirred solution of potassium hydroxide (1.2 g) in ethanol (10 mL)was sequentially added at rt the commercial availablebis(tert.-butyldicarbonyl)amine (4.5 g). After stirring for 1 h at rtthe reaction mixture was quenched with ether and the precipitate wasfiltered and washed with ether (3×10 mL) to afford the title compound(3.4 g)

Step B

The title compound from Step A above (95 mg) was dissolved in CHCl₃(2.25 ml) and 1,3-dimethoxybenzene (0.18 ml) added. To the mixture wasthen added TFA (0.75 ml) and the mixture was stirred at rt for 1 h 30min. The mixture was concentrated, dissolved in CH₃CN (3 ml) andconcentrated again. The residue was dissolved in 100 mM HCl (3 ml) andEtOAc (3 ml). The aqueous phase was separated, washed with EtOAc (2 ml)and concentrated. The residue was suspended in CH₃CN (1.5 ml), sonicatedfor 1 min and the CH₃CN removed by syringe. The residue was then driedin HV to afford the title compound (42 mg, 84%, MH⁺=154).

Preparative Example 91

Step A

To a solution of the commercial available Boc-Fmoc-protected amino acid(1.05 g) in methanol (25 ml) was added diethyl amine (1.5 ml). Afterstirring for 2.5 h at room temperature the reaction mixture wasconcentrated, and the residue was dissolved in water (50 ml) and Et₂O(50 ml). The organic phase was extracted with water (3×50 ml) and thecombined aqueous extracts were concentrated. The residue was used forthe next step without any further purification.

Step B

To a solution of the title compound from Step A above (530 mg) and3-fluorobenzaldehyde (245 μl) in 15 ml of methanol was added NaBH₃CN(150 mg), and the mixture was stirred at 25° C. overnight. The mixturewas concentrated, and the residue was dissolved in EtOAc (50 ml). Theorganic layer was extracted with water (3×50 ml) and the combinedaqueous extracts were concentrated. The residue was used for the nextstep without any further purification.

Step C

To a stirring solution of the title compound from Step B above (760 mg)in DMF (20 ml) was added HOBt (470 mg) followed by EDCI (670 mg) andDMAP (30 mg). N-methyl morpholine (440 μl) was added and stirring wascontinued at rt overnight. The solvent was removed in vacuo, the residuediluted with EtOAc and then washed with saturated aqueous NaHCO₃. Theorganic phase was dried over MgSO₄, concentrated and the residuepurified by flash chromatography on silica (CH₂Cl₂/acetone, 9:1) toafford the title compound (430 mg, 60% over 3 steps, MH⁺=321).

Step D

The title compound from Step C above (760 mg) was dissolved in EtOAc (6ml) and a solution of 4 M HCl in dioxane (6 ml) was added. After 2 h themixture was triturated with aqueous NaHCO₃ to pH 7.5 and stirred for 15min at rt. After evaporation of the solvent, the crude product waspurified by flash chromatography on silica (CH₂Cl₂/MeOH, 9:1) to affordthe title compound (420 mg, 80%, MH⁺=221).

Step E

To a solution of the title compound from Step D above (85 mg) in THF (5ml) was added triethylamine (80 μl) and the mixture was stirred for 1 hat 50° C. Then the sulfamidate (240 mg.), prepared according to WO03/037327, was added in one portion at −15° C. and the mixture wasstirred at ambient temperature over 2 d. After the addition of 1 MNH₄HCO₃ solution (5 ml), the mixture was stirred for 30 min. Then anexcess saturated NaHCO₃ solution was added and stirring was continuedfor another 15 min. The mixture was then partitioned between EtOAc andwater and the aqueous phase extracted with EtOAc. The combined organicphase was dried over MgSO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica (CH₂Cl₂/acetone, 9:1) toafford the title compound (135 mg, 79%, MH⁺=422).

Step F

A solution of the title compound from Step E above (135 mg) in MeOH (2.5ml) and THF (5 ml) was treated with 1 N LiOH (1.5 ml) and stirredovernight at rt. The reaction mixture was acidified to pH 4.5 with 2 NHCl and stirred for 15 min at rt. The mixture was then extracted withEtOAc, the organic phase washed with brine, dried over MgSO₄ andevaporated to afford the title compound (125 mg, 96%, MH⁺=408).

Preparative Example 92

Step A

A solution of commercially available N-Boc-trans-4-hydroxyl-L-prolineester (2.93 g) in CH₂Cl₂ (20 ml) was cooled to −30° C. and treated withDIEA (4.8 ml). After the addition of triflic anhydride (2.2 ml), themixture was stirred at −30° C. for 60 min and then treated with asolution of the commercially available amine in CH₂Cl₂ (20 ml). Themixture was allowed to warm to rt overnight. The mixture was dilutedwith CH₂Cl₂ (20 ml), washed with 0.5 M Na₂CO₃ (2×50 ml) and brine (50ml). The organic phase was dried over MgSO₄ and concentrated to leave aresidue, which was purified by chromatography on silica (CH₂Cl₂/acetone,4:1) to afford the title compound (2.22 g, 75%, MH⁺=367).

Step B

A solution of the title compound from Step A above (700 mg) in MeOH (24ml) and THF (12 ml) was treated with 1 N LiOH (6 ml) and stirredovernight at rt. The reaction mixture was acidified to pH 4.5 with 1 NHCl and stirred for 15 min at rt. The mixture was then extracted withEtOAc, the organic phase washed with brine, dried over MgSO₄ andevaporated to afford the title compound (665 mg, 95%, MH⁺=353).

Step C

To a stirring solution of the title compound from Step B above (665 mg)in DMF (15 ml) was added HOBt (390 mg) followed by EDCI (560 mg) andDMAP (30 mg). N-methyl morpholine (420 μl) was added and stirring wascontinued at rt overnight. The solvent was removed in vacuo, the residuediluted with EtOAc and then washed with saturated aqueous NaHCO₃. Theorganic phase was dried over MgSO₄, concentrated and the residuepurified by flash chromatography on silica (CH₂Cl₂/acetone, 9:1) toafford the title compound (556 mg, 87%, MH⁺=335).

Step D

The title compound from Step C above (760 mg) was dissolved in EtOAc (4ml) and a solution of 4 M HCl in dioxane (4 ml) was added. After 2 h themixture was triturated with aqueous NaHCO₃ to pH 7.5 and stirred for 15min at rt. After evaporation of the solvent, the crude residue waspurified by flash chromatography on silica (CH₂Cl₂/MeOH, 9:1) to affordthe title compound (300 mg, 77%, MH⁺=235).

Step E

To a solution of the title compound from Step D above (290 mg) in THF (5ml) was added triethyl amine (280 μl) and the mixture was stirred for 1h at 50° C. Then the sulfamidate (590 mg.), prepared according to WO03/037327, was added in one portion at −15° C. and the mixture wasstirred at ambient temperature over 2 d. After the addition of 1 MNH₄HCO₃ solution (5 ml), the mixture was stirred for 30 min. Then anexcess saturated NaHCO₃ solution was added and stirring was continuedfor another 15 min. The mixture was then partitioned between EtOAc andwater and the aqueous phase extracted with EtOAc. The combined organicphase was dried over MgSO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica (CH₂Cl₂/acetone, 4:1) toafford the title compound (163 mg, 30%, MH⁺=436).

Step F

A solution of the title compound from Step E above (163 mg) in MeOH (2.5ml) and THF (5 ml) was treated with 1 N LiOH (1.5 ml) and stirredovernight at rt. The reaction mixture was acidified to pH 4.5 with 2 NHCl and stirred for 15 min at rt. The mixture was then extracted withEtOAc, the organic phase washed with brine, dried over MgSO₄ andevaporated to afford the title compound (140 mg, 96%, MH⁺=422).

Preparative Example 93

Step A

To a stirring solution of the title compound from Preparative Example 91(25 mg) in DMF (3 ml) was added HOBt (15 mg), followed by EDCI (20 mg)and DMAP (3 mg). Commercially available (S)-Pyrrolidine-2-carbonitrilehydrochloride (15 mg) was added after 1 h, followed by N-methylmorpholine (20 μl). The mixture was stirred at rt overnight, the solventremoved in vacuo, and the residue was diluted with EtOAc. The mixturewas washed with saturated aqueous NaHCO₃, separated, dried over MgSO₄and concentrated. The residue was purified by flash chromatography onsilica (CH₂Cl₂/acetone, 9:1) to afford the title compound (17 mg, 59%,MH⁺=486).

Step B

To a stirring solution of the title compound Preparative Example 91 (125mg) in DMF (5 ml) was HOBt (46 mg), followed by EDCI (65 mg) and DMAP (5mg). After 1 h commercially available L-proline amide (68 mg) andN-methyl morpholine (100 μl) were added and stirring was continued at rtovernight. The solvent was removed in vacuo, the residue diluted withEtOAc and washed with saturated aqueous NaHCO₃. The organic phase wasseparated, dried over MgSO₄ and concentrated. The residue was purifiedby flash chromatography on silica (CH₂Cl₂/acetone, 4:1) to afford thetitle compound (137 mg; 88%; MH⁺=504).

Step C

To a solution of the title compound from Step B above (137 mg) inpyridine (7 ml) was added imidazole (41 mg). At −30° C. POCl₃ (102 μl)was slowly added to the mixture and the mixture was allowed to reach rtover a period of 1 h. Then the solvent was removed and the residuediluted with 1 N HCl and Et₂O. The organic phase was separated, driedover MgSO₄ and evaporated. The residue was purified by columnchromatography on silica (CH₂Cl₂/acetone, 4:1) to afford the titlecompound (72 mg, 55%, MH⁺=486).

Preparative Example 94-108

Following a similar procedure as that described in Preparative Examples92 and 93, except using the amines and amides as indicated in the Tablebelow, the following compound were prepared. For Preparative Examples105 and 106 the conversion of the nitrile to the carboxamide withsubsequent saponification of the ester moiety was done according toPreparative Example 91 Step F with 3M Na₂CO₃ and H₂O₂.

Preparative 1. Yield Example Amide Amine Product 2. MH⁺  94

1. 55% 2. 498  95

1. 90% 2. 537  96

1. 71% 2. 493  97

1. 70% 2. 504  98

1. 73% 2. 516  99

1. 65% 2. 493 100

1. 54% 2. 505 101

1. 78% 2. 493 102

1. 56% 2. 500 103

1. 65% 2. 512 104

1. 71% 2. 514 105

1. 68% 2. 511 106

1. 56% 2. 511 107

1. 62% 2. 526 108

1. 2.

Preparative Example 109

Step A

A solution of commercially available N-Boc-trans-4-hydroxyl-L-prolinemethyl ester (370 mg) in CH₂Cl₂ (2 ml) was cooled to −30° C. and treatedwith DIEA (600 μl). After the addition of triflic anhydride (280 μl),the mixture was stirred at −30° C. for 60 min and then treated with asolution of the title compound from Preparative Example 91 Step D inCH₂Cl₂ (2 ml). The mixture was allowed to warm to rt overnight. Themixture was diluted with CH₂Cl₂ (10 ml), washed with 0.5 M Na₂CO₃ (2×10ml) and brine (10 ml). The organic phase was dried over MgSO₄ andconcentrated to leave a residue, which was purified by chromatography onsilica ((CH₂Cl₂/acetone, 4:1), 4:1) to afford the title compound (225mg, 33%, MH⁺=448).

Step B

A solution of the title compound from Step A above (225 mg) in MeOH (4ml) and THF (8 ml) was treated with 1 N LiOH (2 ml) and stirredovernight at rt. The reaction mixture was acidified to pH 4.5 with 1 NHCl and stirred for 15 min at rt. The mixture was then extracted withEtOAc, the organic phase washed with brine, dried over MgSO₄ andevaporated to afford the title compound (91 mg, 40%, MH⁺=434).

Step C

To a stirring solution of the title compound from Step B above (91 mg)in DMF (3 ml) was added HOBt (40 mg), followed by EDCI (60 mg) and DMAP(10 mg). Commercially available (S)-Pyrrolidine-2-carbonitrilehydrochloride (35 mg) was added after 1 h, followed by N-methylmorpholine (66 μl). The mixture was stirred at rt overnight, the solventremoved in vacuo, and the residue was diluted with EtOAc. The mixturewas washed with saturated aqueous NaHCO₃, separated, dried over MgSO₄and concentrated. The residue was purified by flash chromatography onsilica (CH₂Cl₂/acetone, 1:1) to afford the title compound (50 mg, 47%,MH⁺=512).

Preparative Example 110

Step A

The title compound from Preparative Example 91 Step D (305 mg) wasdissolved in THF (2 ml) was added triethyl amine (63 μl) and the mixturewas stirred for 1 h at 50° C. Then the title compound from PreparativeExample 19 (100 mg) was added in one portion at −15° C. and the mixturewas stirred at ambient temperature overnight. After the addition of 1 MNH₄HCO₃ solution (5 ml), the mixture was stirred for 30 min. Then anexcess saturated NaHCO₃ solution was added and stirring was continuedfor another 15 min. The mixture was then partitioned between EtOAc andwater and the aqueous phase extracted with EtOAc. The combined organicphase was dried over MgSO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica (CH₂Cl₂/acetone, 4:1) toafford the title compound (58 mg, 57%, MH⁺=378).

Step B

The title compound from Step A above (58 mg) was dissolved in EtOAc (2ml) and a solution of 4 M HCl in dioxane (2 ml) was added. After 2 h themixture was evaporated to afford the title compound (48 mg, quant.,MH⁺=278).

Preparative Example 111

Step A

Commercially available N-cyclohexylcarbodiimde-N′-methyl polystyreneresin (1.9 g) was suspended in 5 ml dichloromethane and agitated for 5Min. The commercially available amino acid (468 mg) and amine (86 mg),prepared from the commercially available hydrochloride by adding 1 eq.pyridine, were dissolved in 1.5 ml dimethylformamide and added to theabove resin. The mixture was agitated for 16 h, filtered and the resinwashed with 2×5 ml dichloromethane and 5 ml methanol. The combinedfiltrates were concentrated and the residue purified by flashchromatography (silica, CH₂Cl₂/MeOH, 9:1) to afford the title compound(500 mg; 91%).

¹H-NMR (CDCl₃): δ 1.45 (9H, s), 2.05-2.30 (4H, m), 3.25-3.40 (1H, m),3.50-3.70 (2H, m), 3.80-3.90 (1H, m), 4.15-4.25 (1H, m), 4.30-4.40 (2H,m), 4.55-4.65 (1H, m), 4.70-4.80 (1H, m), 5.50-5.60 (2H, m), 7.25-7.40(4H, m), 7.55-7.65 (2H, m), 7.70-7.80 (2H, m).

Step B

The title compound from Step A above (500 mg) was dissolved indichloromethane (10 ml) and treated with diethylamine (10 ml). After 2 hthe mixture was concentrated and the residue was purified by flashchromatography (silica, CH₂Cl₂/MeOH, 4:1) to afford the title compound(224 mg; 80%).

¹H-NMR (CDCl₃): δ 1.45 (9H, s), 1.70 (2H, s), 2.05-2.30 (4H, m),2.95-3.05 (2H, m), 3.70-3.85 (2H, m), 4.35-4.50 (1H, m), 4.75-4.85 (1H,m), 5.50-5.60 (1H, m).

Preparative Example 112

Step A

A solution of commercially available N-Fmoc-trans-4-hydroxyl-L-proline(4.5 g) in aqueous ethanol (80%, 45 ml) was titrated with a solution ofCs₂CO₃ (2.3 g) in water (18 ml) to pH 7. The solvents were evaporatedand the residue dried in vacuo. The caesium salt was suspended in dryDMF (45 ml), cooled to 0° C. and treated with allyl bromide (11.5 ml) bydropwise addition over 10 min. After 30 min the solution was allowed toreach rt and stirring was continued for another 3 h. The reactionmixture was filtered and concentrated. The residue was purified bychromatography on silica (EtOAc/cyclohexane) to afford the titlecompound (4.5 g, 90%, MH⁺=394).

Step B

The title compound from Step A above (2.5 g) in CH₂Cl₂ (60 ml) wascooled to −30° C. and treated with DIEA (2.5 ml). After the addition oftriflic anhydride (1.2 ml), the mixture was stirred at −30° C. for 60min and then treated with a solution of Preparative Example 84 (1.17 g)in CH₂Cl₂ (15 ml). The mixture was allowed to warm to 0° C., stirred at0° C. for 12 h and refluxed for additional 4 h. The mixture was dilutedwith CH₂Cl₂ (50 ml), washed with 0.5 M Na₂CO₃ (2×25 ml) and brine (25ml). The organic phase was dried over MgSO₄ and concentrated to leave aresidue, which was purified by chromatography on silica(EtOAc/cyclohexane, 7:3) to afford the title compound (1.41 g, 50%,MH⁺=658).

Step C

To the title compound from Step B above (1.8 g) in THF (120 ml) wasadded dimedone (1.27 g) and Pd(PPh₃)₄ (422 mg). The reaction mixture wasstirred at room temperature for 19 h. Following removal of the solventunder reduced pressure, chromatography on silica (CH₂Cl₂/MeOH 9:1)afforded the title compound (1.42 g, 84%, MH⁺=618).

Step D

To a solution of the title compound from Step C above (1.42 g) in CH₂Cl₂(70 ml) was added HOBT (405 mg) followed by EDCI (575 mg) andN-methyl-morpholine (0.33 ml). After being stirred at ambienttemperature for 24 h, the solvent was evaporated to give a viscousresidue, which was partitioned between EtOAc and ammonium acetate buffer(pH 6). The aqueous phase was extracted with ethyl acetate (3×100 ml)and the combined organic phase dried over MgSO₄ and concentrated toafford the title compound (1.35 g, MNH₄ ⁺=617).

Step E

To a solution of the title compound from Step D above (1.35 g) inacetonitrile (100 ml) was added diethyl amine (10 ml). After stirringfor 2.5 h at rt, the reaction mixture was concentrated. The residue waspurified by chromatography on silica (CH₂Cl₂/MeOH, 9:1) to afford thetitle compound (712 mg; 85%, MH⁺=378).

Preparative Example 113

To a solution of the title compound from Preparative Example 112 (13 mg)in CH₂Cl₂ (0.8 ml) was added piperidino methyl polystyrene resin (65 mg)and 3-fluorobenzene-1-sulfonyl chloride (5.5 μl). After shaking at rtfor 3 h, tris-(2-aminoethyl)amine polystyrene resin (30 mg) was addedand agitated for additional 1 h at rt. The mixture was filtered, theresin washed with CH₂Cl₂ (5 ml) and methanol (1 ml) and the combinedfiltrates evaporated. Purification by chromatography on silica(CH₂Cl₂/MeOH 9:1) afforded the title compound (13 mg, 71%, MNH₄ ⁺=553).

Preparative Example 114-116

Following a similar procedure as that described in Preparative Example113, except using the sulfonic acid chlorides as indicated in the Tablebelow, the following compounds were prepared.

Preparative Sulfonic 1. Yield Example acid chloride Product 2. MH⁺ 114

1. 69 2. 541 (MNH₄ ⁺) 115

1. 92 2. 546 (MNa⁺) 116

1. 89 2. 604 (MNa⁺)

Preparative Example 117-119

Following a similar procedure as that described in Preparative Example113, except using the acid chlorides as indicated in the Table below,the following compounds were prepared.

Preparative Acid 1. Yield Example chloride Product 2. MH⁺ 117

1. 100 2. 488 (MH⁺) 118

1. 49 2. 519 (MNH₄ ⁺) 119

1. 70 2. 506 (MNa⁺)

Preparative Example 120

To a solution of the title compound from Preparative Example 112 (20 mg)in CH₂Cl₂ (0.8 ml) was added tert.-butyl isocyanate (5.8 mg). Afterstirring at room temperature for 3 h the solvent was evaporated.Purification by chromatography (CH₂Cl₂/acetone 1:1) afford the titlecompound (16 mg, 63%, MH⁺=477).

Preparative Example 121

Following a similar procedure as that described in Preparative Example120, except using the isocyanate as indicated in the Table below, thefollowing compound was prepared.

Preparative 1. Yield Example Isocyanate Product 2. MH⁺ 121

1. 69 2. 592 (MNH₄ ⁺)

Preparative Example 122

The title compound from Preparative Example 15 Step A (13 mg) wasdissolved in CH₂Cl₂ (0.7 ml) and added to N-cyclohexylcarbodiimide,N′-methyl polystyrene resin (120 mg). The mixture was agitated for 15min and then treated with a solution of the title compound fromPreparative Example 112 (0.54 ml, 7.5 mM CH₂Cl₂). After shaking at rtfor 12 h, the mixture was filtered and the resin washed with CH₂Cl₂ (5ml). The filtrates were concentrated in vacuo to afford the titlecompound (30 mg, 95%, MNa⁺=632).

Preparative Example 123

Step A

Commercially available 2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acidtert-butyl ester (400 mg) and aziridine-1,2-dicarboxylic acid 1-benzylester 2-methyl ester (431 mg) were dissolved in toluene (5 ml). Themixture was stirred at rt overnight and then for 5 h at 80° C. Thesolvent was removed and the residue purified by chromatography on silica(CH₂Cl₂/acetone 9:1) to afford the title compound (468 mg, 58%,MH⁺=434).

Step B

The title compound from Step A above (245 mg) was dissolved in dioxane(5 ml) and a solution of 4 M HCl in dioxane (5 ml) was added. Themixture was stirred for 2 h at rt and the solvents removed to afford thetitle compound (208 mg, 100%, MH⁺=334).

Step C

To the title compound from Step B above (130 mg) were added CH₂Cl₂ (10ml) and pyridine (1 ml). After the addition of commercially availablethiophen-2-yl-acetyl chloride (61 mg) the reaction mixture was stirredat rt overnight. The solvent was removed and the residue purified bychromatography on silica (CH₂Cl₂/acetone 9:1) to afford the titlecompound (90 mg, 57%, MH⁺=458).

Step D

The title compound from Step C above (130 mg) was dissolved in THF (4ml) and methanol (2 ml). After the addition of 1 M aqueous LiOH-solution(1 ml), the mixture was stirred for 4 h at rt. The solvents were removedand the residue dissolved in water and acidified with 1 M HCl to pH˜4.The mixture was extracted with EtOAc, the organic phase washed withbrine, dried over MgSO₄ and concentrated to yield the title compound (75mg, 86%, MH⁺=444).

Step E

The title compound from Step D above (75 mg) was dissolved in DMF (5ml). After the addition of EDCI (38 mg), HOBt (27 mg),N-methylmorpholine (0.15 ml) and DMAP (10 mol %), the mixture wasstirred for 1 h at rt. Then commercially available2-(S)-cyanopyrrolidine hydrochloride was added and the mixture wasstirred overnight at rt. The solvent was removed and the residuedissolved in EtOAc, washed with brine, dried over MgSO₄. andconcentrated. The residue was purified by chromatography on silica(cyclohexane/EtOAc, 7:3) to afford the title compound (27 mg, 30%,MH⁺=522).

Preparative Example 124-125

Following a similar procedure as that described in Preparative Example123, except using the piperazine derivatives and sulfonic acid chloridesas indicated in the Table below, the following compounds were prepared.

Piperazine Sulfonic 1. Yield Example derivative Acid chloride Product 2.MH⁺ 124

1. 73% 2. 556 125

none

1. 27% 2. 492

Preparative Examples 126-129 have been intentionally excluded.

Preparative Example 130

Step A

Commercially available 2-formyl-pyrrolidine-1-carboxylic acid tert-butylester (330 mg) in anhydrous THF (5 ml) was cooled to 0° C. andtrimethyl-trifluoromethylsilane (300 μl) added, followed by addition oftetrabutylammoniumfluoride (60 μl; 1 M in THF). The reaction mixture wasallowed to warm to rt and then stirred for 1 h. After dilution withdiethyl ether, the organic phase was washed with brine and the aqueousphase extracted with diethyl ether. The combined organic phases weredried (MgSO₄) and evaporated to afford the title compounds as a 1:1mixture of alcohol and TMS ether (490 mg, 97%, [MH-Boc]⁺=242 (TMSether); [MH-Boc]⁺=170 (alcohol)).

Step B

The title compounds from Step A above (721 mg) in dichloromethane (5 ml)were added to Dess Martin periodinane (2.32 g) in dichloromethane (15ml) with stirring. Trifluoroacetic acid (410 μl) was added dropwise andthe turbid reaction mixture stirred for 17 h at rt, after which it wasdirectly coated on silica and purified by column chromatography (silica,cyclohexane/EtOAc 90:10->80:20) to afford the title compound (301 mg,45%, [MH-Boc]⁺=168).

Step C

To the title compound from Step B above (106 mg) in dioxane (500 μl) wasadded 4 M HCl in dioxane (500 μl) and the resulting mixture stirred for16 h at rt. Diethyl ether was added (2 ml) and the suspension filtered.The precipitate was dried and the title compound obtained as its HClsalt (81 mg, 91%, MH⁺=186).

Preparative Examples 131-199 have been intentionally excluded.

Preparative Example 200-294

If one were to follow a similar procedure as that described inPreparative Example 61 and in Preparative Example 44, except using thesulfamidates as indicated in the Table below in Step A of PreparativeExample 61, one would obtain the title compounds, listed in thefollowing Table in the “product” column.

Preparative Preparative Example Example Sulfamidate Product 200 24

201 25

202 26

203 27

204 28

205 29

206 30

207 31

208 32

209 33

210 34

211 35

212 36

213 37

214 38

215 39

216 40

217 41

218 42

219 43

220 44

221 45

222 46

223 24

224 23

225 25

226 26

227 27

228 28

229 29

230 30

231 31

232 32

233 33

234 34

235 35

236 36

237 37

238 38

239 39

240 40

241 41

242 42

243 43

244 44

245 45

246 46

247 24

248 23

249 25

250 26

251 27

252 28

253 29

254 30

255 31

256 32

257 33

258 34

259 35

260 36

261 37

262 38

263 39

264 40

265 41

266 42

267 43

268 44

269 45

270 46

271 24

272 23

273 25

274 26

275 27

276 28

277 29

278 30

279 31

280 32

281 33

282 34

283 35

284 36

285 37

286 38

287 39

288 40

289 41

290 42

291 43

292 44

293 45

294 46

Examples 295-299 have been intentionally excluded.

Preparative Example 300

Step A

If one were to treat the compound from Preparative Example 59 with thesulfimidate from Preparative Example 22 according to the proceduredescribed in Preparative Example 61 Step A, one would obtain the titlecompound.

Step B

If one were to treat the title compound from Step A above with NaN₃ asdescribed in Preparative Example 61 Step B, one would obtain the titlecompound.

Step C

If one were to treat the title compound from Step B above with aceticacid anhydride in pyridine at 100° C. for 2 h one would obtain, afterthe removal of the pyridine under reduced pressure and after columnchromatography, the title compound.

Step D

If one were to treat the title compound from Step A above according tothe procedures described in Preparative Example 70 one would obtain thetitle compound.

Preparative Example 301-335

If one were to follow a similar procedure as that described inPreparative Example 300, except using the appropriate intermediate fromthe Preparative Examples and anhydrides or acid chlorides and amines asindicated in the Table below, one would obtain the desired amineproduct.

Preparative Preparative Acid Chloride/ Example Example Anhydride AmineProduct 301 300

NH₃

302 300

NH₃

303 300

NH₃

304  61

NH₃

305  61

NH₃

306  61

NH₃

307  61

NH₃

308  65

NH₃

309  65

NH₃

310  65

NH₃

311  65

NH₃

312 300

CH₃NH₂

313 300

CH₃NH₂

314 300

CH₃NH₂

315 300

CH₃NH₂

316  61

CH₃NH₂

317  61

CH₃NH₂

318  61

CH₃NH₂

319  61

CH₃NH₂

320  65

CH₃NH₂

321  65

CH₃NH₂

322  65

CH₃NH₂

323  65

CH₃NH₂

324 300

(CH₃)₂NH

325 300

(CH₃)₂NH

326 300

(CH₃)₂NH

327 300

(CH₃)₂NH

328  61

(CH₃)₂NH

329  61

(CH₃)₂NH

330  61

(CH₃)₂NH

331  61

(CH₃)₂NH

332  65

(CH₃)₂NH

333  65

(CH₃)₂NH

334  65

(CH₃)₂NH

335  65

(CH₃)₂NH

Example numbers 336-399 were intentionally excluded.

Preparative Example 400-434

If one were to follow a similar procedure as that described inPreparative Example 66, except using the appropriate intermediate fromthe Preparative Examples and hydroxylamine hydrochlorides and amines asindicated in the Table below and treat the products according toPreparative Example 70, one would obtain the desired amine product.

Preparative Preparative Hydroxylamine Example Example hydrochlorideAmine Product 400 300

NH₃

401 300

NH₃

402 300

NH₃

403 300

NH₃

404  61

NH₃

405  61

NH₃

406  61

NH₃

407  61

NH₃

408  65

NH₃

409  65

NH₃

410  65

NH₃

411  65

NH₃

412 300

CH₃NH₂

413 300

CH₃NH₂

414 300

CH₃NH₂

415 300

CH₃NH₂

416  61

CH₃NH₂

417  61

CH₃NH₂

418  61

CH₃NH₂

419  61

CH₃NH₂

420  65

CH₃NH₂

421  65

CH₃NH₂

422  65

CH₃NH₂

423  65

CH₃NH₂

424 300

(CH₃)₂NH

425 300

(CH₃)₂NH

426 300

(CH₃)₂NH

427 300

(CH₃)₂NH

428  61

(CH₃)₂NH

429  61

(CH₃)₂NH

430  61

(CH₃)₂NH

431  65

(CH₃)₂NH

432  65

(CH₃)₂NH

433  65

(CH₃)₂NH

434  65

(CH₃)₂NH

Example numbers 435-499 were intentionally excluded.

Preparative Example 500

Step A

If one were to treat the compound from Preparative Example 300 Step Awith conc. HCl in acetic acid according to the procedure described inPreparative Example 49 Step J, one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above according tothe procedure described in Preparative Example 70 Step A, one wouldobtain the title compound.

Step C

If one were to treat the title compound from Step B above according tothe procedure described in Preparative Example 70 Step A but usinghydrazine instead of an amine, one would obtain the title compound.

Step D

If one were to stir the title compound from Step C above with 1 eq.ethyl isocyanate in DMA one would obtain after removing of DMA and thetitle compound.

Step E

If one were to treat the title compound from Step D above with a 2%aqueous NaOH at 100° C. for several hours one would obtain afterneutralisation, precipitation and recrystallisation from ethanol thetitle compound.

Step F

If one were to treat the title compound from Step E above according tothe procedure described in Preparative Example 70 Step B, one wouldobtain the title compound.

Preparative Example 501-535

If one were to follow a similar procedure as that described inPreparative Example 500, except using the appropriate intermediate fromthe Preparative Examples and hydrazines and amines as indicated in theTable below, one would obtain the desired amine product.

Preparative Preparative Example Example Hydrazine Amine Product 501 300

NH₃

502 300

NH₃

503 300

NH₃

504 61 N₂H₄ NH₃

505 61

NH₃

506 61

NH₃

507 61

NH₃

508 65 N₂H₄ NH₃

509 65

NH₃

510 65

NH₃

511 65 NH₃

512 300 N₂H₄ CH₃NH₂

513 300

CH₃NH₂

514 300

CH₃NH₂

515 300

CH₃NH₂

516 61 N₂H₄ CH₃NH₂

517 61

CH₃NH₂

518 61

CH₃NH₂

519 61

CH₃NH₂

520 65 N₂H₄ CH₃NH₂

521 65

CH₃NH₂

522 65

CH₃NH₂

523 65

CH₃NH₂

524 300 N₂H₄ (CH₃)₂NH

525 300

(CH₃)₂NH

526 300

(CH₃)₂NH

527 300

(CH₃)₂NH

528 61 N₂H₄ (CH₃)₂NH

529 61

(CH₃)₂NH

530 61

(CH₃)₂NH

531 61

(CH₃)₂NH

532 65 N₂H₄ (CH₃)₂NH

533 65

(CH₃)₂NH

534 65

(CH₃)₂NH

535 65

(CH₃)₂NH

Example numbers 536-599 were intentionally excluded.

Preparative Example 600

Step A

If one were to treat the intermediate from Preparative Example 300 StepA with dry HCl gas in EtOH/CHCl₃ at 0° C. and set aside for 10 days, onewould obtain after removal of the solvents the imidate hydrochloride. Ifone were to treat the imidate hydrochloride with NH₃ in dry EtOH andheat it to reflux for 7 h, one would obtain, after filtration andevaporation of the filtrate followed by recrystallization, the titlecompound.

Step B

If one were to treat the title compound from Step A above with Boc₂Oaccording to the procedure described in Preparative Example 49 Step Jbut without the acid treatment, one would obtain the title compound.

Step C

If one were to treat the title compound from Step B above according toPreparative Example 61 Step C, one would obtain the title compound.

Step D

If one were to treat the title compound from Step C above according tothe procedures described in Preparative Example 70, one would obtain thetitle compound.

Preparative Example 601-635

If one were to follow a similar procedure as that described inPreparative Example 600 except using the amines and appropriateintermediate from the Preparative Examples as indicated in the Tablebelow, one would obtain the desired amine product.

Preparative Preparative Amine Amine Example Example Step A Step BProduct 601 300 CH₃NH₂ NH₃

602 300

NH₃

603 300

NH₃

604 61 NH₃ NH₃

605 61 CH₃NH₂ NH₃

606 61

NH₃

607 61

NH₃

608 65 NH₃ NH₃

609 65 CH₃NH₂ NH₃

610 65

NH₃

611 65

NH₃

612 300 NH₃ CH₃NH₂

613 300 CH₃NH₂ CH₃NH₂

614 300

CH₃NH₂

615 300

CH₃NH₂

616 61 NH₃ CH₃NH₂

617 61 CH₃NH₂ CH₃NH₂

618 61

CH₃NH₂

619 61

CH₃NH₂

620 65 NH₃ CH₃NH₂

621 65 CH₃NH₂ CH₃NH₂

622 65

CH₃NH₂

623 65

CH₃NH₂

624 300 NH₃ (CH₃)₂NH

625 300 CH₃NH₂ (CH₃)₂NH

626 300

(CH₃)₂NH

627 300

(CH₃)₂NH

628 61 NH₃ (CH₃)₂NH

629 61 CH₃NH₂ (CH₃)₂NH

630 61

(CH₃)₂NH

631 61

(CH₃)₂NH

632 65 NH₃ (CH₃)₂NH

633 65 CH₃NH₂ (CH₃)₂NH

634 65

(CH₃)₂NH

635 65

(CH₃)₂NH

Example numbers 636-679 were intentionally excluded.

Preparative Example 680-687

If one were to follow a similar procedure as that described inPreparative Example 67 and 70, except using the appropriate intermediatefrom the Preparative Examples and amines as indicated in the Tablebelow, one would obtain the desired amine product.

Prepa- rative Preparative Example Example Amine Product 680 300 NH₃

681 61 NH₃

682 65 NH₃

683 300 CH₃NH₂

684 61 CH₃NH₂

685 65 CH₃NH₂

686 300 (CH₃)₂NH

687 65 (CH₃)₂NH

Example numbers 688-699 were intentionally excluded.

Preparative Example 700

Step A

If one were to treat the compound from Preparative Example 300 Step Awith hydroxylamine hydrochloride and base according to PreparativeExample 67 Step A, one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above according toPreparative Example 67 Step B, one would obtain the title compound.

Step C

If one were to treat the title compound from step B above withLawesson's Reagent in toluene and heat the mixture to reflux for 4 h,one would obtain after column chromatography the title compound.

Step D

If one were to treat the title compound from Step C above with formicacid hydrazide (Pellizzari-Synthesis), one would obtain the titlecompound.

Step E

If one were to treat the title compound from Step D above according tothe procedures described in Preparative Example 70, one would obtain thetitle compound.

Preparative Example 701-735

If one were to follow a similar procedure as that described inPreparative Example 700, except using the appropriate intermediate fromthe Preparative Examples, acid hydrazides and amines as indicated in theTable below, one would obtain the desired amine product.

Preparative Preparative Acid Example Example hydrazide Amine Product 701300

NH₃

702 300

NH₃

703 300

NH₃

704 61

NH₃

705 61

NH₃

706 61

NH₃

707 61

NH₃

708 65

NH₃

709 65

NH₃

710 65

NH₃

711 65

NH₃

712 300

CH₃NH₂

713 300

CH₃NH₂

714 300

CH₃NH₂

715 300

CH₃NH₂

716 61

CH₃NH₂

717 61

CH₃NH₂

718 61

CH₃NH₂

719 61

CH₃NH₂

720 65

CH₃NH₂

721 65

CH₃NH₂

722 65

CH₃NH₂

723 65

CH₃NH₂

724 300

(CH₃₎₂NH

725 300

(CH₃₎₂NH

726 300

(CH₃₎₂NH

727 300

(CH₃₎₂NH

728 61

(CH₃₎₂NH

729 61

(CH₃₎₂NH

730 61

(CH₃₎₂NH

731 61

(CH₃₎₂NH

732 65

(CH₃₎₂NH

733 65

(CH₃₎₂NH

734 65

(CH₃₎₂NH

735 65

(CH₃₎₂NH

Example numbers 736-779 were intentionally excluded.

Preparative Example 780

If one were to treat the starting material, which was obtained bytreating the title compound from Preparative Example 300 Step Aaccording to the procedures described in Preparative Example 500 StepA-C, according to the procedure described in Preparative Example 70 StepB, one would obtain the title compound.

Preparative Example 781-788

If one were to follow a similar procedure as that described inPreparative Example 780, except using the appropriate intermediate fromthe Preparative Examples and amines as indicated in the Table below, onewould obtain the desired amine product.

Preparative Preparative Example Example Amine Product 781 61 NH₃

782 65 NH₃

783 300 CH₃NH₂

784 61 CH₃NH₂

785 65 CH₃NH₂

786 300 (CH₃)₂NH

787 61 (CH₃)₂NH

788 65 (CH₃)₂NH

Example numbers 789-799 were intentionally excluded.

Preparative Example 800

Step A

If one were to treat commercial available N methyl anthranilic acid with2 eq. of 2-bromo-5-chloronitrobenzene, 10 eq. of potassium carbonate anda catalytic amount of copper powder in 3-methylbutan-1-ol under refluxfor several hours one would obtain, after removing of the volatilecompound by steam distillation, acidification of the residue with 2 MHCl, precipitation and recrystallisation of the precipitate fromethanol, the title compound.

Step B

If one were to treat the title compound from Step A above with 7 eq. ofsodium dithionite in 2 M aqueous ammonia at 80° C. one would obtain,after filtration, acidification of the filtrate with glacial acetic acidto pH 4, precipitation and recrystallisation from methanol, the titlecompound.

Step C

If one were to reflux the title compound from Step B above in xyleneunder Dean Stark conditions one would obtain, after evaporation of thesolvent, washing of the residue with 2 M aqueous ammonia andrecrystallisation from acetone, the title compound.

Step D

If one were to treat the title compound from Step C above with thesulfamidate from Preparative Example 22 according to Preparative Example61 Step A one would obtain the title compound.

Step E

If one were to treat the title compound from Step A above with TFA asdescribed in Preparative Example 70 Step B, one would obtain the titlecompound.

Preparative Example 801-805

If one were to follow a similar procedure as that described inPreparative Example 800, except using the diazepines and sulfamidates asindicated in the Table below, one would obtain the desired amineproduct.

Preparative Example Diazepine Sulfamidate Product 801

22

802

21

803

24

804

21

805

24

Examples 806-809 have been intentionally excluded.

Preparative Example 810

Step A

If one were to treat commercially available10,10-dimethyl-10H-anthracen-9-one and concentrated sulphuric acid inchloroform in a flask equipped with reflux condenser with sodium azideat room temperature, followed by heating this mixture at 50° C. andsubsequently pouring it on crushed ice followed by neutralization withconc. aqueous ammonia, separation and evaporation of the organic phase,one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above with thesulfamidate from Preparative Example 22 as described in PreparativeExample 800, one would obtain the title compound.

Preparative Example 811-812

If one were to follow a similar procedure as described in PreparativeExample 810, except using the azepines and sulfamidates as indicated inthe able below, one would obtain the desired amine product.

Preparative Example Azepine Sulfamidate Product 811

24

812

21

Examples 813-829 have been intentionally excluded.

Preparative Example 830

Step AA

If one were to add a solution of commercially available2-amino-2-methyl-1-propanol in methylene chloride to a solution ofcommercially available 2-thiophenecarbonyl chloride in methylenechloride dropwise while maintaining the temperature below 20° C.,subsequently stir the mixture at room temperature for 2 h and wash withwater, dry the organic layer (MgSO₄) and evaporate, suspend the residuein toluene and add thionyl chloride dropwise with stirring whilemaintaining the temperature below 30° C., subsequently continue thestirring overnight, evaporate the toluene, dissolve the residue inwater, basify with 1 N aqueous NaOH and extract with ether, then, afterdrying (MgSO₄) and evaporation of the solvent, followed by distillation,one would obtain the title compound.

Step BB

If one were to add commercial -nBuLi in hexane to the title compoundfrom Step AA above in ether at −78° C., stir the mixture under argon for0.25 h, add DMF, allow the mixture to slowly warm to room temperatureand leave the mixture at this temperature for 18 h, subsequently addwater and ether, separate the organic solution, wash with water, brineand dry the solution (MgSO₄), then, after evaporation of the solvent,followed by chromatographic purification, one would obtain the titlecompound.

Step CC

If one were to boil the title compound from Step BB above under refluxwith 4M aqueous hydrochloric acid under argon atmosphere for 14 h,saturate the cooled solution with NaCl, extract repeatedly with ethylacetate, dry the combined organic extracts (MgSO₄), then, afterevaporation of the solvent, followed by recrystallization from ethylacetate/hexane, one would obtain the title compound.

Step DD

If one were to treat the title compound from Step CC above in methanoldropwise with an ethereal solution of diazomethane at −15° C., followedby careful removal of all volatiles, then one would obtain the titlecompound.

Step A

If one were to add commercially available methyl4-methylthiophene-2-carboxylate to N-bromosuccinimide, benzoyl peroxideand tetrachloromethane and would heat the mixture under reflux for 4 hfollowed by filtration and evaporation of the solvent, one would obtainthe title compound.

Step B

If one were to treat the title compound from Step A above withtriphenylphosphine according to Preparative Example 51 Step C, one wouldobtain the title compound.

Step C

If one were to treat the title compound from Step B above with thethiophene aldehyde from Step DD as described in Preparative Example 54Step A, one would obtain the title compound.

Step D

If one were to treat a suspension of the title compound from Step Cabove, hydroiodic acid and red phosphorus at 140° C. for 18 h, followedby cooling and pouring the reaction mixture into an ice/water mixture,subsequent filtration, washing of the precipitate with water, dissolvingthe precipitate in refluxing conc. ammonia and subsequent filtration,acidification of the filtrate with conc. aqueous hydrochloric acid andextraction of the aqueous phase with dichloromethane, washing of theorganic phase with water and drying (MgSO₄) followed by evaporation ofthe solvent, one would obtain the title compound.

Step E

If one were to treat a suspension of the title compound from Step Dabove with polyphosphoric acid at 170° C., followed by cooling to 30°C., pouring into water, extraction with diethyl ether, washing with 1Naqueous sodium hydroxide solution and drying (MgSO₄) followed byevaporation of the solvent, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E above as describedin Preparative Example 59 Step G, one would obtain the title compound.

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 59 Step H and Step I, one would obtain the titlecompound.

Step H

If one were to treat the title compound from Step G above with thecompound from Preparative Example 22 as described in Preparative Example61 Step A, one would obtain the title compound.

Step I

If one were to treat the title compound from Step H above as describedin Preparative Example 61 Step B, one would obtain the title compound.

Step J

If one were to treat the title compound from Step I above as describedin Preparative Example 61 Step C, one would obtain the title compound.

Preparative Example 831

Step A

If one were to treat the title compound from Preparative Example 830 asdescribed in Preparative Example 71 Step A, one would obtain the titlecompound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 71 Step B, one would obtain the title compound.

Preparative Example 832-839

If one were to follow a similar procedure as that described inPreparative Example 830, except using the sulfamidates in Step H, andtreat the product obtained according to Preparative Example 831 with theamine as indicated in the table below, one would obtain the desiredtitle compound as HCl salts.

Preparative Example Sulfamidate Amine Title compound 831 21 NH₃

832 24 NH₃

833 22 NH₃

834 21 CH₃NH₂

835 24 CH₃NH₂

836 22 CH₃NH₂

837 24 (CH₃)₂NH

838 22 (CH₃)₂NH

Examples 839 to 849 have been intentionally excluded.

Preparative Example 850

Step AA

If one were to treat commercially available thiophene-3-carbaldehydewith bromine and aluminium trichloride in dichloromethane and heat thereaction mixture for 2 h, subsequently pouring it into water, followedby extraction with ether, washing of the organic phase successively withaqueous 1N NaOH solution and water until neutral, then, after drying(MgSO₄) and evaporation of the solvent, followed by distillation, onewould obtain the title compound.

Step BB

If one were to treat a solution of the title compound from Step AA abovein tetrahydrofuran with NaBH₄ for 1 h and quench the reaction by theaddition of saturated aqueous ammonium chloride solution followed bydilution with ethyl acetate, separation of the organic layer, washingwith H₂O and brine, then, after drying (MgSO₄) and evaporation of thesolvent, one would obtain the title compound.

Step CC

If one were to treat a solution of the title compound from Step BB abovein chloroform with thionyl chloride at room temperature for 4 h,subsequently pouring it into water, followed by extraction withchloroform, washing of the organic phase with water, then, after drying(MgSO₄) and evaporation of the solvent, one would obtain the titlecompound.

Step A

If one were to treat commercially available 2-bromo-3-methylthiophene inacetic acid with N-chlorosuccinimide and stir the reaction mixture forabout 2 h, then refluxing it for 1 h, subsequently pouring it intowater, followed by extraction with ether, washing of the organic phasesuccessively with aqueous 1N NaOH solution and water until neutral,then, after drying (MgSO₄) and evaporation of the solvent, followed bydistillation, one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 59 Step A, one would obtain the title compound.

Step C

If one were to treat the title compound from Step B above with the titlecompound from Step CC above, as described in Preparative Example 59 StepB, one would obtain the title compound.

Step D

If one were to treat the title compound from Step C above as describedin Preparative Example 59 Step C, one would obtain the title compound.

Step E

If one were to treat the title compound from Step D above as describedin Preparative Example 59 Step D, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E above as describedin Preparative Example 59 Step E and Step F, one would obtain the titlecompound.

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 59 Step G, one would obtain the title compound.

Step H

If one were to treat the title compound from Step G above as describedin Preparative Example 59 Step H and Step I, one would obtain the titlecompound.

Step I

If one were to treat the title compound from Step H above as describedin Preparative Example 61 Step A, one would obtain the title compound.

Step J

If one were to treat the title compound from Step I above as describedin Preparative Example 61 Step B, one would obtain the title compound.

Step K

If one were to treat the title compound from Step J above as describedin Preparative Example 61 Step C, one would obtain the title compound.

Preparative Example 851

Step A

If one were to treat the title compound from Preparative Example 851 asdescribed in Preparative Example 71 Step A one would obtain the titlecompound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 71 Step B, one would obtain the title compound.

Preparative Example 852-859

If one were to follow a similar procedure as that described inPreparative Example 850, except using the sulfamidates in Step I, andtreat the product obtained according to Preparative Example 851 with theamine as indicated in the table below, one would obtain the desiredtitle compound as HCl salt.

Preparative Example Sulfamidate Amine Title compound 852 21 NH₃

853 24 NH₃

854 22 NH₃

855 21 CH₃NH₂

856 24 CH₃NH₂

857 22 CH₃NH₂

858 24 (CH₃)₂NH

859 22 (CH₃)₂NH

Examples 860-899 have been intentionally excluded.

Preparative Example 900

Step AA

If one were to add a solution of commercially available2-(3bromo-2-thienyl)-1,3-dioxolane in dry diethylether with stirring to1.05 N butyl lithium in diethylether at −70° C., followed by addition ofthe mixture to solid CO₂ covered with diethylether. Hydrolysis, followedby extraction with diluted aqueous sodium hydroxide, acidification, thenextraction with diethylether afford the title compound.

Step BB

If one were to add H₂SO₄ and methanol to a solution of the titlecompound from step AA above in dichloroethane, one would obtain thetitle compound.

Step A

If one were to treat a solution of commercially available5-methylthiophene-2-carboxylic acid in benzene and methanol at 0° C.dropwise with 2.0 M trimethylsilyldiazo-methane in hexanes, one wouldobtain the methyl ester. If one were to treat a solution of that esterintermediate in CCl₄ with NBS and 2,2′-azobisisobutyronitrile (AIBN) andheat the solution to reflux for 2 h, followed by cooling down to roomtemperature, filtration and concentration in vacuo one would obtain thetitle compound.

Step B

If one were to treat the title compound from Step A above withtriphenylphosphine according to Preparative Example 49 Step C, one wouldobtain the title compound.

Step C

If one were to treat the title compound from Step B above with the titlecompound from Step BB above as described in Preparative Example 54 StepA, one would obtain the title compound.

Step D

If one were to heat a mixture of the title compound from Step C, redphosphorous and hydroiodic acid in acetic acid at 110° C. for 1 h, onewould obtain a solution after filtration of the hot mixture. Aftercooling to room temperature and pouring in ice water one would obtainthe title compound by suction.

Step E

If one were to heat a mixture of the title compound from Step D aboveand polyphosphoric acid at 115° C. for 1.5 h one would obtain a mixture,which was poured on ice. After extraction with Ether washing the organicphases with water, drying (MgSO₄) and removing of the solvent one wouldobtain the title compound.

Step F

If one were to treat the title compound from Step E above as describedin Preparative Example 59 Step G, one would obtain the title compound.

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 59 Step H and Step I, one would obtain the titlecompound.

Step H

If one were to treat the title compound from Step G above with thecompound from Preparative Example 22 as described in Preparative Example61 Step A, one would obtain the title compound.

Step I

If one were to treat the title compound from Step H above as describedin Preparative Example 61 Step B, one would obtain the title compound.

Step J

If one were to treat the title compound from Step I above as describedin Preparative Example 61 Step C, one would obtain the title compound.

Preparative Example 901

Step A

If one were to treat the title compound from Preparative Example 900 asdescribed in Preparative Example 71 Step A, one would obtain the titlecompound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 71 Step B, one would obtain the title compound.

Preparative Example 902-909

If one were to follow a similar procedure as that described inPreparative Example 900, except using the sulfamidates in Step H, andtreat the product obtained according to Preparative Example 901 with theamines as indicated in the table below, one would obtain the desiredtitle compound as HCl salt.

Preparative Example Sulfamidate Amine Title compound 902 21 NH₃

903 24 NH₃

904 22 NH₃

905 21 CH₃NH₂

906 24 CH₃NH₂

907 22 CH₃NH₂

908 24 (CH₃)₂NH

909 22 (CH₃)₂NH

Examples 910-919 have been intentionally excluded.

Preparative Example 920

Step A

If one were to add a solution of bromine in CHCl₃ slowly to anice-cooled solution of commercially available 2-chloro-5-methylthiophenein CHCl₃ one would obtain a reaction mixture which was stirred for 2 hat room temperature, and subsequently poured into H₂O. If one were toextract than the mixture with dichloromethane combine the organicextracts dry filter and evaporate the solvent, one would obtain ayellow/brown oil.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 59 Step A, one would obtain the title compound.

Step C

If one were to treat the title compound from Step B above withcommercially available 2-chloro-5-chloromethyl-thiophene as described inPreparative Example 59 Step B, one would obtain the title compound.

Step D

If one were to treat the title compound from Step C above as describedin Preparative Example 59 Step C, one would obtain the title compound.

Step E

If one were to treat the title compound from Step D above as describedin Preparative Example 59 Step D, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E above as describedin Preparative Example 59 Step E and Step F, one would obtain the titlecompound.

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 59 Step G, one would obtain the title compound.

Step G

If one were to treat the title compound from Step G above as describedin Preparative Example 59 Step H and Step I, one would obtain the titlecompound.

Step I

If one were to treat the title compound from Step H above as describedin Preparative Example 61 Step A, one would obtain the title compound.

Step J

If one were to treat the title compound from Step I above as describedin Preparative Example 61 Step B, one would obtain the title compound.

Step K

If one were to treat the title compound from Step J above as describedin Preparative Example 61 Step C, one would obtain the title compound.

Preparative Example 921

Step A

If one were to treat the title compound from Preparative Example 920 asdescribed in Preparative Example 71 Step A one would obtain the titlecompound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 71 Step B, one would obtain the title compound.

Preparative Example 922-929

If one were to follow a similar procedure as that described inPreparative Example 920, except using the sulfamidates in Step I, andtreat the product obtained according to Preparative Example 921 with theamine as indicated in the table below, one would obtain the desiredtitle compound as HCl salt.

Preparative Example Sulfamidate Amine Title compound 922 21 NH₃

923 24 NH₃

924 22 NH₃

925 21 CH₃NH₂

926 24 CH₃NH₂

927 22 CH₃NH₂

928 24 (CH₃)₂NH

929 22 (CH₃)₂NH

Examples 930-999 have been intentionally excluded.

Preparative Example 1000-1209

If one were to follow similar procedure as described in PreparativeExamples 92 and 93, except using the amides and amines as indicated inthe Table below, the following title compound would be obtained.

Prep Example Amide Amines Title compound 1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

1028

1029

1030

1031

1032

1033

1034

1035

1036

1037

1038

1039

1040

1041

1042

1043

1044

1045

1046

1047

1048

1049

1050

1051

1052

1053

1054

1055

1056

1057

1058

1059

1060

1061

1062

1063

1064

1065

1066

1067

1068

1069

1070

1071

1072

1073

1074

1075

1076

1077

1078

1079

1080

1081

1082

1083

1084

1085

1086

1087

1088

1089

1090

1091

1092

1093

1094

1095

1096

1097

1098

1099

1100

1101

1102

1103

1104

1105

1106

1107

1108

1109

1110

1111

1112

1113

1114

1115

1116

1117

1118

1119

1120

1121

1122

1123

1124

1125

1126

1127

1128

1129

1130

1131

1132

1133

1134

1135

1136

1137

1138

1139

1140

1141

1142

1143

1144

1145

1146

1147

1148

1149

1150

1151

1152

1153

1154

1155

1156

1157

1158

1159

1160

1161

1162

1163

1164

1165

1166

1167

1168

1169

1170

1171

1172

1173

1174

1175

1176

1177

1178

1179

1180

1181

1182

1183

1184

1185

1186

1187

1188

1189

1190

1191

1192

1193

1194

1195

1196

1197

1198

1199

1200

1201

1202

1203

1204

1205

1206

1207

1208

1209

Examples 1210-1299 have been intentionally excluded.

Preparative Example 1300

Step A

If one were to treat commercially available anthraquinone with 1.5-2equivalents of bromine and some iodine at 160° C., and then treat themixture with aqueous sodium hydroxide at reflux, one would obtain thetitle compound, after crystallisation from glacial acetic acid.

Step B

If one were to treat the title compound from Step A above with hotconcentrated H₂SO₄, treat the obtained solution with Al powder at rt andstir the mixture at rt for 3 h, one would obtain the title compound,after aqueous workup and chromatography on silica gel.

Step C

If one were to treat the title compound from Step B above as describedin Preparative Example 59 Step D, Step E and Step F, one would obtainthe title compound.

Step D

If one were to treat the title compound from Step C above as describedin Preparative Example 59 Step G, one would obtain the title compound.

Step E

If one were to treat the title compound from Step D above as describedin Preparative Example 59 Step H, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E above as describedin Preparative Example 59 Step I, one would obtain the title compound.

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 61 Step A, one would obtain the title compound.

Step H

If one were to treat the title compound from Step G above as describedin Preparative Example 61 Step B, one would obtain the title compound.

Step I

If one were to treat the title compound from Step H above as describedin Preparative Example 61 Step C, one would obtain the title compound.

Preparative Example 1301

Step A

If one were to treat the title compound from Preparative Example 1300 asdescribed in Preparative Example 71 Step A one would obtain the titlecompound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 71 Step B, one would obtain the title compound.

Preparative Example 1302-1309

If one were to follow a similar procedure as that described inPreparative Example 1300, except using the sulfamidates in Step G, andtreat the product obtained according to Preparative Example 1301 withthe amine as indicated in the table below, one would obtain the desiredtitle compound as HCl salt.

Preparative Example Sulfamidate Amine Title compound 1302 21 NH₃

1303 24 NH₃

1304 22 NH₃

1305 21 CH₃NH₂

1306 24 CH₃NH₂

1307 22 CH₃NH₂

1308 24 (CH₃)₂NH

1309 22 (CH₃)₂NH

Examples 1310-1349 have been intentionally excluded.

Preparative Example 1350

Step A

If one were to treat a solution of commercially available4-chloroanthranilic acid in water and concentrated hydrochloric acid at0° C. with a solution of sodium nitrate in water over 45 min and stirthe resulting mixture at 0° C. for 1 h, one would obtain the diazoniumsalt solution after filtration. If one were to treat a solution ofcommercially available hydroxylamine hydrochloride in water at 10° C.with an aqueous solution of sodium hydroxide and carefully pour themixture into an aqueous solution of hydrated copper(II) sulfate andconcentrated ammonia solution, one would obtain a blue solution afterfiltration. If one were to carefully add the diazonium salt solutionfrom above to the blue solution over a period of 1 h and then heat themixture at reflux, followed by the addition of concentrated hydrochloricacid, one would obtain a precipitate after 3 h. If one were to collectthe precipitate by filtration, wash it with water and dissolved it in asolution of sodium bicarbonate, one would obtain a clear solution aftertreatment with charcoal and filtration. If one were to add an excess of6 M aqueous hydrochloric acid and collect the precipitate, one wouldobtain the title compound after crystallisation from EtOH.

Step B

If one were to treat the title compound of Step A above at 400° C. fortwenty-five minutes and then sublime the mixture at 250° C. under apressure of 2 mm, one would obtain the title compound aftercrystallization from benzene.

Step C

If one were to treat the title compound from Step B above as describedin Preparative Example 59 Step D, Step E and Step F, one would obtainthe title compound.

Step D

If one were to treat the title compound from Step C above as describedin Preparative Example 59 Step G, one would obtain the title compound.

Step E

If one were to treat the title compound from Step D above as describedin Preparative Example 59 Step H, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E above as describedin Preparative Example 59 Step I, one would obtain the title compound.

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 61 Step A, one would obtain the title compound.

Step H

If one were to treat the title compound from Step G above as describedin Preparative Example 61 Step B, one would obtain the title compound.

Step I

If one were to treat the title compound from Step H above as describedin Preparative Example 61 Step C, one would obtain the title compound.

Preparative Example 1351

Step A

If one were to treat the title compound from Preparative Example 1350 asdescribed in Preparative Example 71 Step A one would obtain the titlecompound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 71 Step B, one would obtain the title compound.

Preparative Example 1352-1359

If one were to follow a similar procedure as that described inPreparative Example 1350, except using the sulfamidates in Step G, andtreat the product obtained according to Preparative Example 1351 withthe amine as indicated in the table below, one would obtain the desiredtitle compound as HCl salt.

Preparative Example Sulfamidate Amine Title compound 1352 21 NH₃

1353 24 NH₃

1354 22 NH₃

1355 21 CH₃NH₂

1356 24 CH₃NH₂

1357 22 CH₃NH₂

1358 24 (CH₃)₂NH

1359 22 (CH₃)₂NH

Examples 1360-1399 have been intentionally excluded.

Preparative Example 1400

Step A

If one were to treat commercially available 4-bromo benzaldehydedissolved in ether at 0° C. over a period of two hours portion-wise withKCN and concentrated HCl and maintain the temperature of the reactionbelow 10° C., followed by stirring for 1 h after complete addition,while permitting the temperature to rise to 15° C., subsequently theresultant two-phase system is filtered off and washed with ether,separating the combined organic solutions one would obtain theintermediate after washing with saturated aqueous sodium bisulfide,drying over MgSO₄, and concentrating in vacuo. If one were to dilute theresidue with benzene and slowly add this mixture over a period of onehour to concentrated H₂SO₄, which would maintained under stirring in anice bath at a temperature below 15° C. until completion of the addition,followed by stirring for an additional hour, allowing the mixture towarm to room temperature one would obtain after pouring the reactionmixture onto ice and the mixture is being extracted with benzene, thetitle compound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 61 Step A, one would obtain the title compound.

Step C

If one were to treat the title compound from Step B above as describedin Preparative Example 61 Step B, one would obtain the title compound.

Step D

If one were to treat the title compound from Step C above as describedin Preparative Example 59 Step D, Step E and Step F, one would obtainthe title compound.

Step E

If one were to treat the title compound from Step D above as describedin Preparative Example 61 Step C, one would obtain the title compound.

Preparative Example 1401

Step A

If one were to treat the title compound from Preparative Example 1400 asdescribed in Preparative Example 71 Step A one would obtain the titlecompound.

Step B

If one were to treat the title compound from Step A above as describedin Preparative Example 71 Step B, one would obtain the title compound.

Preparative Example 1402-1409

If one were to follow a similar procedure as that described inPreparative Example 1400, except using the sulfamidates in Step B, andtreat the product obtained according to Preparative Example 1401 withthe amine as indicated in the table below, one would obtain the desiredtitle compound as HCl salt.

Preparative Example Sulfamidate Amine Title compound 1402 21 NH₃

1403 24 NH₃

1404 22 NH₃

1405 21 CH₃NH₂

1406 24 CH₃NH₂

1407 22 CH₃NH₂

1408 24 (CH₃)₂NH

1409 22 (CH₃)₂NH

Examples 1410-1449 have been intentionally excluded.

Preparative Example 1450

Step A

If one were to add commercially available diethylmethylmalonate to asolution of sodium ethoxide in EtOH, and then add a solution ofα,α′-dibromo-m-xylene in benzene to the above solution and boil themixture at reflux for 1 h, one would obtain the title compound afterdistillation and crystallisation.

Step B

If one were to treat the title compound from Step A above withaqueous-ethanolic potassium hydroxide, one would obtain the crudetetracarboxylic acid. If one were to decarboxylate the crudetetracarboxylic acid at 210° C., one would obtain the title compound.

Step C

If one were to convert the title compound from Step B above to itsbis-acid chloride with thionyl chloride in benzene and treat thebis-acid chloride with a solution of diazomethane in ether, one wouldobtain the diazoketone intermediate after 12 h and evaporation of thesolvents. If one were to treat the diazoketone with benzylalcohol-γ-collidine (1:1) in an oil-bath maintained at 180° C. for 10Min, one would obtain the crude title compound. If one were to treat thecrude title compound with MeOH and HCl, one would obtain thedimethylester. If one were to treat the diemthylester with KOH in EtOH,one would obtain the title compound.

Step D

If one were to treat the title compound from Step C above withphosphorus pentachloride in benzene for 1 h and warm the mixture on asteam-bath for 5 min, one would obtain the crude bis-acid chloride. Ifone were to dissolve the bis-acid chloride in nitrobenzene, add asolution of aluminium chloride in nitrobenzene at 0° C. and then allowthe mixture to stand at rt for 6 h, one would obtain the title compound,after removal of the nitrobenzene by steam distillation andcrystallisation of the residue with EtOH.

Step E

If one were to treat the title compound from Step D above with hydrazinehydrate and potassium hydroxide in diethylene glycol for 4 h at 180° C.,followed by purification by chromatography on alumina one would obtainthe title compound.

Step F

If one were to treat the title compound from Step E with 10 eq. ofaluminium chloride by adding the compound to the reagent intetrachloroethane at low temperature, add dropwise 2.0 eq. of aceticanhydride to the mixture, pour onto ice and hydrochloric acid andextract with an appropriate solvent, wash with water, evaporate,recrystallize from methanol, one would obtain the title compound.

Step G

If one were to treat the title compound from Step F above with seleniumdioxide in water and dioxane and refluxed for 4 h, followed by removalof precipitated selenium one would obtain after recrystallizaiton thetitle compound.

Step H

If one were to treat the title compound from Step G above with hydrogenperoxide and drop wise with 10% NaOH in ethanol at 80° C., followed bydilution with water, treatment with norite, filtration and acidifyingwith HCl, one would obtain after recrystallization the title compound.

Step I

If one were to treat the title compound from Step H above as describedin Preparative Example 70 Step A, one would obtain the title compound

Step J

If one were to treat the title compound from Step I above as describedin Preparative Example 93 Step C, one would obtain the title compound.

Step K

If one were to treat the title compound from Step J above as describedin Preparative Example 13 Step B, one would obtain the title compound.

Step L

If one were to treat the title compound from Step K above withdiisobutylaluminum hydride in CH₂Cl₂ at −78° C., add 10% aq AcOH,extract with ether:hexane, wash with H₂O, sat. aq NaHCO₃, and brine, dryover Na₂SO₄, evaporate, purify the crude product through chromatographyon silica gel, one would obtain the title compound.

Step M

If one were to treat the title compound from Step L above with 1.2 eq.commercially available methylmagnesium bromide in Et₂O at roomtemperature, heat the mixture to reflux, add ice and half concentratedhydrochlorid acid, extract with Et₂O, wash the organic layer with H₂O,sat. aq NaHCO₃, and brine, dry over Na₂SO₄, evaporate, purify the crudeproduct through chromatography on silica gel, one would obtain the titlecompound.

Step N

If one were to treat the title compound from Step M above withmethylsulfonyl chloride and triethylamine in CH₂Cl₂ at 0° C., evaporate,add water and ethyl acetate to the residue, extract with ethyl acetate,wash the organic layer with H₂O, sat. aq NaHCO₃, and brine, dry overNa₂SO₄, evaporate and then the obtained intermediate with NaN₃ in DMA asdescribed in Preparative Example 17 Step C, one would obtain the titlecompound.

Step O

If one were to treat the title compound from Step N above as describedin Preparative Example 17 Step D, one would obtain the title compound.

Preparative Example 1451

Step A

If one were to treat the title compound from Preparative Example 1450Step E with 10 eq. of aluminium chloride by adding the compound to thereagent in tetrachloroethane at low temperature, add dropwise 2.0 eq. ofacetic anhydride to the mixture, pour onto ice and hydrochloric acid andextract with an appropriate solvent, wash with water, evaporate,recrystallize from methanol, one would obtain the title compound.

Step B

If one were to treat the title compound from Step F above with seleniumdioxide in water and dioxane and refluxed for 4 h, followed by removalof precipitated selenium one would obtain after recrystallizaiton thetitle compound.

Step C

If one were to treat the title compound from Step G above with hydrogenperoxide and drop wise with 10% NaOH in ethanol at 80° C., followed bydilution with water, treatment with norite, filtration and acidifyingwith HCl, one would obtain after recrystallization the title compound.

Step D

If one were to treat the title compound from Step H above as describedin Preparative Example 70 Step A, one would obtain the title compound

Step E

If one were to treat the title compound from Step Iabove as described inPreparative Example 93 Step C, one would obtain the title compound.

Step F

If one were to treat the title compound from Step J above as describedin Preparative Example 13 Step B, one would obtain the title compound.

Step G

If one were to treat the title compound from Step K above withdiisobutylaluminium hydride in CH₂Cl₂ at −78° C., add 10% aq AcOH,extract with ether:hexane, wash with H₂O, sat. aq NaHCO₃, and brine, dryover Na₂SO₄, evaporate, purify the crude product through chromatographyon silica gel, one would obtain the title compound.

Step H

If one were to treat the title compound from Step L above with 1.2 eq.commercially available methylmagnesium bromide in Et₂O at roomtemperature, heat the mixture to reflux, add ice and half concentratedhydrochlorid acid, extract with Et₂O, wash the organic layer with H₂O,sat. aq NaHCO₃, and brine, dry over Na₂SO₄, evaporate, purify the crudeproduct through chromatography on silica gel, one would obtain the titlecompound.

Step I

If one were to treat the title compound from Step M above withmethylsulfonyl chloride and triethylamine in CH₂Cl₂ at 0° C., evaporate,add water and ethyl acetate to the residue, extract with ethyl acetate,wash the organic layer with H₂O, sat. aq NaHCO₃, and brine, dry overNa₂SO₄, evaporate and then the obtained intermediate with NaN₃ in DMA asdescribed in Preparative Example 17 Step C, one would obtain the titlecompound.

Step J

If one were to treat the title compound from Step N above as describedin Preparative Example 17 Step D, one would obtain the title compound.

Preparative Example 1452

Step A

If one were to treat commercially available1,2,3,4,5,6,7,8-octahydro-anthracene with 10 eq. of aluminium chlorideby adding the compound to the reagent in tetrachloroethane at lowtemperature, add dropwise 2.0 eq. of acetic anhydride to the mixture,pour onto ice and hydrochloric acid and extract with an appropriatesolvent, wash with water, evaporate, recrystallize from methanol, onewould obtain the title compound.

Step B

If one were to treat the title compound from Step A above with seleniumdioxide in water and dioxane and refluxed for 4 h, followed by removalof precipitated selenium one would obtain after recrystallization thetitle compound.

Step C

If one were to treat the title compound from Step B above with hydrogenperoxide and drop wise with 10% NaOH in ethanol at 80° C., followed bydilution with water, treatment with norite, filtration and acidifyingwith HCl, one would obtain after recrystallization the title compound.

Step D

If one were to treat the title compound from Step C above as describedin Preparative Example 70 Step A, one would obtain the title compound

Step E

If one were to treat the title compound from Step D above as describedin Preparative Example 93 Step C, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E above as describedin Preparative Example 13 Step B, one would obtain the title compound.

Step G

If one were to treat the title compound from Step F above withdiisobutylaluminium hydride in CH₂Cl₂ at −78° C., add 10% aq AcOH,extract with ether:hexane, wash with H₂O, sat. aq NaHCO₃, and brine, dryover Na₂SO₄, evaporate, purify the crude product through chromatographyon silica gel, one would obtain the title compound.

Step H

If one were to treat the title compound from Step G above with 1.2 eq.commercially available methylmagnesium bromide in Et₂O at roomtemperature, heat the mixture to reflux, add ice and half concentratedhydrochlorid acid, extract with Et₂O, wash the organic layer with H₂O,sat. aq NaHCO₃, and brine, dry over Na₂SO₄, evaporate, purify the crudeproduct through chromatography on silica gel, one would obtain the titlecompound.

Step I

If one were to treat the title compound from Step H above withmethylsulfonyl chloride and triethylamine in CH₂Cl₂ at 0° C., evaporate,add water and ethyl acetate to the residue, extract with ethyl acetate,wash the organic layer with H₂O, sat. aq NaHCO₃, and brine, dry overNa₂SO₄, evaporate and then the obtained intermediate with NaN₃ in DMA asdescribed in Preparative Example 17 Step C, one would obtain the titlecompound.

Step J

If one were to treat the title compound from Step I above as describedin Preparative Example 17 Step D, one would obtain the title compound.

Preparative Example 1453

Step A

If one were to treat commercially available 2-methyl-1H-indene and with0.01 eq of platinum oxide in tetrahydrofuran and hydrogenate at 20-30psi for 10-15 h at room temperature, filter the mixture through a pad ofCelite, purify the crude product through chromatography on silica gel,one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above with 1.0 eq.of 3-chloro-2-methyl-propionyl chloride and 3.0 eq. of aluminum chloridein nitromethane at room temperature, decompose the mixture with ice andhydrochloric acid, dilute with water, filter, dissolve the solid inbenzene and wash with dilute hydrochloric acid, evaporate, purify with aSoxhlet extractor, one would obtain the title compound.

Step C

If one were to treat the title compound from Step B above withconcentrated sulphuric acid by adding the compound in small portions tothe acid at low temperature, heat on the steam-bath, pour onto ice andextract with benzene and water, evaporate, distillate at reducedpressure, recrystallize from petroleum ether, sublimate, one wouldobtain the title compound.

Step D

If one were to treat the title compound from Step C above withamalgamated zinc, water, acetic acid, toluene, hydrochloric acid,separate the organic layer, evaporate, distillate at reduced pressure,recrystallize, one would obtain the title compound.

Step E

If one were to treat the title compound from Step D with 10 eq. ofaluminium chloride by adding the compound to the reagent intetrachloroethane at low temperature, add dropwise 2.0 eq. of aceticanhydride to the mixture, pour onto ice and hydrochloric acid andextract with an appropriate solvent, wash with water, evaporate,recrystallize from methanol, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E with an aqueoussolution of potassium hypochlorite prepared from bleaching powder inmethanol, separate the precipitate formed by filtration, acidify thefiltrate, separate the precipitate formed by filtration, recrystallizefrom methanol, one would obtain the title compound.

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 70 Step A, one would obtain the title compound

Step H

If one were to treat the title compound from Step G above as describedin Preparative Example 93 Step C, one would obtain the title compound.

Step I

If one were to treat the title compound from Step H above withdiisobutylaluminium hydride in CH₂Cl₂ at −78° C., add 10% aq AcOH,extract with ether:hexane, wash with H₂O, sat. aq NaHCO₃, and brine, dryover Na₂SO₄, evaporate, purify the crude product through chromatographyon silica gel, one would obtain the title compound.

Step J

If one were to treat the title compound from Step H above as describedin Preparative Example 13 Step B, one would obtain the title compound.

Step K

If one were to treat the title compound from Step I above with 1.2 eq.commercially available methylmagnesium bromide in Et₂O at roomtemperature, heat the mixture to reflux, add ice and half concentratedhydrochlorid acid, extract with Et₂O, wash the organic layer with H₂O,sat. aq NaHCO₃, and brine, dry over Na₂SO₄, evaporate, purify the crudeproduct through chromatography on silica gel, one would obtain the titlecompound.

Step L

If one were to treat the title compound from Step K above withmethylsulfonyl chloride and triethylamine in CH₂Cl₂ at 0° C., evaporate,add water and ethyl acetate to the residue, extract with ethyl acetate,wash the organic layer with H₂O, sat. aq NaHCO₃, and brine, dry overNa₂SO₄, evaporate and then the obtained intermediate with NaN₃ in DMA asdescribed in Preparative Example 17 Step C, one would obtain the titlecompound.

Step M

If one were to treat the title compound from Step L above as describedin Preparative Example 17 Step D, one would obtain the title compound.

Preparative Example 1454

Step A

If one were to treat commercially available indane with 1.0 eq. of3-chloro-propionyl chloride and 3.0 eq. of aluminum chloride innitromethane at room temperature, decompose the mixture with ice andhydrochloric acid, dilute with water, filter, dissolve the solid inbenzene and wash with dilute hydrochloric acid, evaporate, purify with aSoxhlet extractor, one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above withconcentrated sulphuric acid by adding the compound in small portions tothe acid at low temperature, heat on the steam-bath, pour onto ice andextract with benzene and water, evaporate, distillate at reducedpressure, recrystallize from petroleum ether, sublimate, one wouldobtain the title compound.

Step C

If one were to treat the title compound from Step B above withamalgamated zinc, water, acetic acid, toluene, hydrochloric acid,separate the organic layer, evaporate, distillate at reduced pressure,recrystallize, one would obtain the title compound.

Step D

If one were to treat the title compound from Step D with 10 eq. ofaluminium chloride by adding the compound to the reagent intetrachloroethane at low temperature, add dropwise 2.0 eq. of aceticanhydride to the mixture, pour onto ice and hydrochloric acid andextract with an appropriate solvent, wash with water, evaporate,recrystallize from methanol, one would obtain the title compound.

Step E

If one were to treat the title compound from Step D with an aqueoussolution of potassium hypochlorite prepared from bleaching powder inmethanol, separate the precipitate formed by filtration, acidify thefiltrate, separate the precipitate formed by filtration, recrystallizefrom methanol, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E above as describedin Preparative Example 70 Step A, one would obtain the title compound

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 93 Step C, one would obtain the title compound.

Step H

If one were to treat the title compound from Step G above withdiisobutylaluminium hydride in CH₂Cl₂ at −78° C., add 10% aq AcOH,extract with ether:hexane, wash with H₂O, sat. aq NaHCO₃, and brine, dryover Na₂SO₄, evaporate, purify the crude product through chromatographyon silica gel, one would obtain the title compound.

Step I

If one were to treat the title compound from Step G above as describedin Preparative Example 13 Step B, one would obtain the title compound.

Step J

If one were to treat the title compound from Step H above with 1.2 eq.commercially available methylmagnesium bromide in Et₂O at roomtemperature, heat the mixture to reflux, add ice and half concentratedhydrochloride acid, extract with Et₂O, wash the organic layer with H₂O,sat. aq NaHCO₃, and brine, dry over Na₂SO₄, evaporate, purify the crudeproduct through chromatography on silica gel, one would obtain the titlecompound.

Step K

If one were to treat the title compound from Step J above withmethylsulfonyl chloride and triethylamine in CH₂Cl₂ at 0° C., evaporate,add water and ethyl acetate to the residue, extract with ethyl acetate,wash the organic layer with H₂O, sat. aq NaHCO₃, and brine, dry overNa₂SO₄, evaporate and then the obtained intermediate with NaN₃ in DMA asdescribed in Preparative Example 17 Step C, one would obtain the titlecompound.

Step L

If one were to treat the title compound from Step K above as describedin Preparative Example 17 Step D, one would obtain the title compound.

Examples 1455-1499 have been intentionally excluded.

Preparative Example 1500

Step A

If one were to treat commercially available 1,4-benzoquinone withbuta-1,3-diene in benzene at 100° C. in an autoclave, separate theprecipitate, wash it with methanol, one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above with LiAlH₄ inTHF at rt for 15 min and then heat to reflux for 50 min, one wouldobtain after removal of the solvent, followed by aqueous workup andcolumn chromatography the title compound.

Step C

If one were to treat the title compound from Step B above withmethanesulfonyl chloride in pyridine at 0° C. for 24 h, one would obtainafter pouring into an ice/water mixture followed by extraction withbenzene and subsequently washing the organic phase with water, cold 5%sulphuric acid, water, 2% sodium bicarbonate solution, brine and finallyevaporation to dryness, the methansulfonate intermediate. If one were totreat the methansulfonate intermediate with LiAlH₄ in THF and heat toreflux for 24 h, one would obtain after removal of the solvent, followedby aqueous workup the alcohol intermediate.

If one were to treat the alcohol intermediate with CrO₃ in pyridine at40° C. for 9 h, one would obtain after pouring into water, followed byextraction with CCl₄ and subsequently drying the organic phase andevaporating to dryness, followed by column chromatography andcrystallization the alkene intermediate. If one were to treat the alkeneintermediate with Pd/C in ethanol at 10 bar H₂ and room temperature,separate the crude product from the reaction mixture and then theobtained intermediate with CrO₃ in aqueous acetic acid and water,neutralize the mixture, extract with Et₂O, recrystallize fromTHF/CH₂Cl₂, one would obtain the title compound.

Step D

If one were to treat the title compound from Step C above as describedin Preparative Example 59 Step G, one would obtain the title compound.

Step E

If one were to treat the title compound from Step D above as describedin Preparative Example 59 Step H, one would obtain the title compound.

Step F

If one were to treat the title compound from Step E with NaCN in 90%ethanol under reflux, add water, extract with CHCl₃, wash the organiclayer with 5% sulphuric acid, sat. aq NaHCO₃, water, brine, dry overNa₂SO₄, distillate, one would obtain the title compound.

Step G

If one were to treat the title compound from Step F above as describedin Preparative Example 61 Step A, one would obtain the title compound.

Step H

If one were to treat the title compound from Step G above as describedin Preparative Example 61 Step B, one would obtain the title compound.

Step I

If one were to treat the title compound from Step H above as describedin Preparative Example 70 Step B, one would obtain the title compound.

Preparative Example 1501-1502

If one were to follow a similar procedure as that described inPreparative Example 1500, except using the sulfamidates in Step G, onewould obtain the desired title compound as HCl salt.

Preparative Example Sulfamidate Title compound 1501 22

1502 24

Example 1

The title compound from Preparative Example 5 (378 mg) and 419 mg K₂CO₃were suspended in 3 ml THF and cooled to 0° C. A solution of PreparativeExample 1 (109 mg) in 1 ml THF was slowly added and the reaction mixturestirred at 0° C. for 2 h and then at rt overnight. The mixture wasdiluted with 30 ml EtOAc and 10 ml H₂O, the organic phase separated,dried over MgSO₄ and concentrated. The residue was purified bychromatography on silica (CH₂Cl₂/MeOH, 4:1) to afford the title compound(66 mg; 39%; MH⁺=389).

Example 2-14

Following a similar procedure as that described in Example 1, exceptusing the compounds from the Preparative Examples indicated in the Tablebelow, the following compounds were prepared.

Compound Compound Preparative Preparative 1. Yield Example ExampleExample Product 2. MH⁺ 2 1  6

1. 17% 2. 346 3 1  7

1. 8% 2. 417 4 1 13

1. 19% 2. 360 5 1 14 Step B

1. 18% 2. 389 6 1 14

1. 15% 2. 375 7 1 15 Step C

1. 8% 2. 372 8 1 15

1. 8% 2. 374 9 1 16

1. 16% 2. 389 10 1 17 Step D

1. 7% 2. 390 11 1 17

1. 8% 2. 372 12 1 10

1. 16% 2. 429 13 1 11

1. 19% 2. 415 14 1 12

1. 19% 2. 401

Example 15

An aliquot of the title compound of Preparative Example 3 was taken andthe solvent removed. The residue (67 mg) was dissolved in DMF (2 ml) andtriethylamine (0.1 ml). The title compound from Preparative Example 90(71 mg) was added and the mixture was stirred at 60° C. for 2 h. Thesolvent was removed and the residue was purified by preparative TLC(CHCl₃/MeOH (+0.1% Triethylamine), 4:1) to afford the title compound (12mg; 13%; MH⁺=381).

Example 16

The title compound from Preparative Example 18 Step B (100 mg) andPreparative Example 2 (68 mg) were dissolved in 2 ml EtOH and 1 ml H₂O.The pH of the solution was adjusted to pH˜6 by adding 0.1 M HCl-solutionand the mixture was stirred at rt for 10 min. After the addition ofNaCNBH₃ (24 mg) the pH was maintained at pH˜6 by the addition of 0.1 MHCl and the mixture was stirred at rt overnight. The mixture was dilutedwith 30 ml EtOAc and 15 ml sat. NaHCO₃/brine (1:1), the organic phaseseparated, dried over MgSO₄ and concentrated. The residue was purifiedby Prep TLC(CH₂Cl₂/MeOH, 95:5) to afford the title compound (25.9 mg;17%; MH⁺=399).

Example 17-47

Following a similar procedure as described in Example 16 by dissolvingthe amine in a EtOH/H₂O— or MeOH/H₂O-mixture and adjusting the pH topH˜6-8 by either 0.1 M HCl, 3 M NaOAc or 1 M NaOH, except using thecompounds from the Preparative Examples indicated in the Table below,the following compounds were prepared. In case the reaction was notcompleted after 24 h as judged by HPLC, additional aldehyde fromPreparative Example 2 or 89 and NaCNBH₃ were added, and the reaction wascontinued for another 1-3 days.

For the products obtained, the following purification methods wereemployed:

-   Method A: chromatography on silica using CH₂Cl₂/MeOH-mixtures; or-   Method B: product was precipitated from the reaction mixture by    adding 1 M HCl to pH 1-3 and the precipitate washed with MeOH; or-   Method C: reaction mixture was concentrated to half its volume and    the crude product purified by reverse phase HPLC (21.5×250 mm,    Phenomenex, Luna C-18 (2), 5 μM; flow=15 ml/min or 10×250 mm,    Phenomenex, Luna C-18 (2), 5 μM; flow=3 ml/min) using acetonitrile    (solvent B; 0.1% formic acid) and H₂O (solvent A; 0.1% formic acid)    as eluents and a suitable gradient, ramping solvent B from 0% to    100% over a period of 18 min.

Compound Compound Preparative Preparative Purification 1. Yield ExampleExample Example Method Product 2. MH⁺ 17 2 18 A

1. 17% 2. 417 18 2 47 A

1. 41% 2. 431 19 2 48 A

1. 18% 2. 431 20 2 8 A

1. 25% 2. 424 21 2 9 A

1. 18% 2. 390 22 2 49 A

1. 21% 2. 478 23 2 50 B

1. 30% 2. 442 24 2 51 B

1. 5% 2. 478 25 2 87 B

1. 46% 2. 510 26 2 110 A

1. 15% 2. 414 27 2 70 C

1. 36% 2. 542 28 2 72 C

1. 14% 2. 570 29 2 71 C

1. 38% 2. 598 30 2 73 C

1. 21% 2. 598 31 2 74 C

1. 8% 2. 626 32 2 75 C

1. 58% 2. 622 33 2 76 C

1. 9% 2. 682 34 2 56 C

1. 11% 2. 528 35 2 77 C

1. 7% 2. 556 36 2 78 C

1. 10% 2. 584 37 2 79 C

1. 12% 2. 556 38 2 80 C

1. 43% 2. 614 39 2 81 C

1. 2% 2. 573 40 2 82 C

1. 26% 2. 666 41 2 83 C

1. 12% 2. 542 42 2 84 C

1. 10% 2. 542 43 2 85 C

1. 60% 2. 572 44 2 86 C

1. 28% 2. 544 45 2 52 C

1. 14% 2. 503 46 2 88 C

1. 2% 2. 471 47 89 56 C

1. 9% 2. 540

Example 48

The title compound from Preparative Example 93 (16 mg) was dissolved ina mixture of H₂O (3 ml) and a solution of 4 M HCl in dioxane (3 ml).After 20 h the reaction mixture was diluted with toluene. The organiclayer was evaporated to afford the title compound (14 mg; 99%; MH⁺=386).

Example 49-64

Following a similar procedure as that described in Example 48, exceptusing the compounds from the Preparative Examples indicated in the Tablebelow, the following compound was prepared.

Compound Preparative 1. Yield Example Example Product 2. MH⁺ 49 95

1. 77% 2. 436 50 96

1. 92% 2. 393 51 97

1. 89% 2. 404 52 98

1. 96% 2. 416 53 99

1. 57% 2. 393 54 100

1. 95% 2. 404 55 101

1. 93% 2. 393 56 102

1. 98% 2. 400 57 108

1. 96% 2. 400 58 103

1. 95% 2. 412 59 104

1. 95% 2. 414 60 105

1. 92% 2. 411 61 106

1. 95% 2. 411 62 107

1. 81% 2. 426 63 109

1. 85% 2. 412 64 94

1. 95% 2. 398

Example 65

The title compound from Preparative Example 113 (13 mg) was treated with4 M HCl in dioxane as described in Example 47 to afford the titlecompound (11.2 mg, 98%, MH⁺=436).

Example 66-75

Following a similar procedure as that described in Example 65, exceptusing the compounds from the Preparative Examples indicated in the Tablebelow, the following compounds were prepared.

Compound Preparative 1. Yield Example Example Product 2. MH⁺ 66 114

1. 100 2. 424 67 115

1. 33 2. 424 68 116

1. 40 2. 482 69 117

1. 85 2. 388 70 118

1. 96 2. 402 71 119

1. 84 2. 384 72 122

1. 30 2. 510 73 112 Step D

1. 50 2. 500 74 121

1. 97 2. 475 75 120

1. 100 2. 377

Example 76

The title compound from Preparative Example 123 (27 mg) was dissolved indichloromethane (2 ml) and trimethylsilyl iodine (21 mg) was added. Themixture was stirred for 1 h at room temperature. After removal of thesolvent the residue was purified by preparative TLC to afford thedesired compound (CHCl₃/MeOH, 4 mg, 20%, MH⁺=388).

Examples 77-78

Following a similar procedure as that described in Example 76, exceptusing the compounds from the Preparative Examples as indicated in theTable below, the following compounds were prepared.

Preparative 1. Yield Example Example Product 2. MH⁺ 77 124

1. 10% 2. 422 78 125

1. 11% 2. 358

Examples 79-99 have been intentionally excluded.

Example 100-184

If one were to follow the procedures outlined in Preparative Example 71and Examples 28 or 29 but using the amines, carboxylic acids andaldehydes from the Preparative Examples as indicated in the Table below,one would obtain the indicated Product.

Example Carboxylic # Amine Acid Aldehyde Product 100

Prep Ex 62 Prep Ex 2 

101

Prep Ex 62 Prep Ex 2 

102

Prep Ex 62 Prep Ex 2 

103

Prep Ex 62 Prep Ex 2 

104

Prep Ex 62 Prep Ex 2 

105

Prep Ex 62 Prep Ex 2 

106

Prep Ex 62 Prep Ex 2 

107

Prep Ex 62 Prep Ex 2 

108

Prep Ex 62 Prep Ex 2 

109

Prep Ex 62 Prep Ex 2 

110 NH₃ Prep Ex 55 Prep Ex 2 

111 MeNH₂ Prep Ex 55 Prep Ex 2 

112 (Me)₂NH Prep Ex 55 Prep Ex 2 

113

Prep Ex 55 Prep Ex 2 

114

Prep Ex 55 Prep Ex 2 

115

Prep Ex 55 Prep Ex 2 

116

Prep Ex 55 Prep Ex 2 

117

Prep Ex 55 Prep Ex 2 

118

Prep Ex 55 Prep Ex 2 

119

Prep Ex 55 Prep Ex 2 

120

Prep Ex 55 Prep Ex 2 

121

Prep Ex 55 Prep Ex 2 

122

Prep Ex 55 Prep Ex 2 

123

Prep Ex 65 Prep Ex 2 

124

Prep Ex 65 Prep Ex 2 

125

Prep Ex 65 Prep Ex 2 

126

Prep Ex 65 Prep Ex 2 

127

Prep Ex 65 Prep Ex 2 

128

Prep Ex 65 Prep Ex 2 

129

Prep Ex 65 Prep Ex 2 

130

Prep Ex 65 Prep Ex 2 

131

Prep Ex 65 Prep Ex 2 

132

Prep Ex 61 Prep Ex 2 

133

Prep Ex 61 Prep Ex 2 

134

Prep Ex 61 Prep Ex 2 

135

Prep Ex 61 Prep Ex 2 

136

Prep Ex 61 Prep Ex 2 

137

Prep Ex 61 Prep Ex 2 

138 MeNH₂ Prep Ex 62 Prep Ex 89

139 (Me)₂NH Prep Ex 62 Prep Ex 89

140

Prep Ex 62 Prep Ex 89

141

Prep Ex 62 Prep Ex 89

142

Prep Ex 62 Prep Ex 89

143

Prep Ex 62 Prep Ex 89

144

Prep Ex 62 Prep Ex 89

145

Prep Ex 62 Prep Ex 89

146

Prep Ex 62 Prep Ex 89

147

Prep Ex 62 Prep Ex 89

148

Prep Ex 62 Prep Ex 89

149

Prep Ex 62 Prep Ex 89

150 NH₃ Prep Ex 55 Prep Ex 89

151 MeNH₂ Prep Ex 55 Prep Ex 89

152 (Me)₂NH Prep Ex 55 Prep Ex 89

153

Prep Ex 55 Prep Ex 89

154

Prep Ex 55 Prep Ex 89

155

Prep Ex 55 Prep Ex 89

156

Prep Ex 55 Prep Ex 89

157

Prep Ex 55 Prep Ex 89

158

Prep Ex 55 Prep Ex 89

159

Prep Ex 55 Prep Ex 89

160

Prep Ex 55 Prep Ex 89

161

Prep Ex 55 Prep Ex 89

162

Prep Ex 55 Prep Ex 89

163

Prep Ex 65 Prep Ex 89

164

Prep Ex 65 Prep Ex 89

165

Prep Ex 65 Prep Ex 89

166

Prep Ex 65 Prep Ex 89

167

Prep Ex 65 Prep Ex 89

168

Prep Ex 65 Prep Ex 89

169

Prep Ex 65 Prep Ex 89

170

Prep Ex 65 Prep Ex 89

171

Prep Ex 65 Prep Ex 89

172 NH₃ Prep Ex 61 Prep Ex 89

173 MeNH₂ Prep Ex 61 Prep Ex 89

174 (Me)₂NH Prep Ex 61 Prep Ex 89

175

Prep Ex 61 Prep Ex 89

176

Prep Ex 61 Prep Ex 89

177

Prep Ex 61 Prep Ex 89

178

Prep Ex 61 Prep Ex 89

179

Prep Ex 61 Prep Ex 89

180

Prep Ex 61 Prep Ex 89

181

Prep Ex 61 Prep Ex 89

182

Prep Ex 61 Prep Ex 89

183

Prep Ex 61 Prep Ex 89

184

Prep Ex 61 Prep Ex 89

Examples 185-199 have been intentionally excluded.

Example 200-389

If one were to follow the procedures outlined in Examples 28 or 29except using the compounds from the Preparative Examples as indicated inthe Table below, one would obtain the indicated Product.

Preparative Preparative Example Example Example Product 200 200 2

201 201 2

202 202 2

203 203 2

204 204 2

205 205 2

206 206 2

207 207 2

208 208 2

209 209 2

210 210 2

211 211 2

212 212 2

213 213 2

214 214 2

215 215 2

216 216 2

217 217 2

218 218 2

219 219 2

220 220 2

221 221 2

222 222 2

223 223 2

224 224 2

225 225 2

226 226 2

227 227 2

228 228 2

229 229 2

230 230 2

231 231 2

232 232 2

233 233 2

234 234 2

235 235 2

236 236 2

237 237 2

238 238 2

239 239 2

240 240 2

241 241 2

242 242 2

243 243 2

244 244 2

245 245 2

246 246 2

247 247 2

248 248 2

249 249 2

250 250 2

251 251 2

252 252 2

253 253 2

254 254 2

255 255 2

256 256 2

257 257 2

258 258 2

259 259 2

260 260 2

261 261 2

262 262 2

263 263 2

264 264 2

265 265 2

266 266 2

267 267 2

268 268 2

269 269 2

270 270 2

271 271 2

272 272 2

273 273 2

274 274 2

275 275 2

276 276 2

277 277 2

278 278 2

279 279 2

280 280 2

281 281 2

282 282 2

283 283 2

284 284 2

285 285 2

286 286 2

287 287 2

288 288 2

289 289 2

290 290 2

291 291 2

292 292 2

293 293 2

294 294 2

295 200 89

296 201 89

297 202 89

298 203 89

299 204 89

300 205 89

301 206 89

302 207 89

303 208 89

304 209 89

305 210 89

306 211 89

307 212 89

308 213 89

309 214 89

310 215 89

311 216 89

312 217 89

313 218 89

314 219 89

315 220 89

316 221 89

317 222 89

318 223 89

319 224 89

320 225 89

321 226 89

322 227 89

323 228 89

324 229 89

325 230 89

326 231 89

327 232 89

328 233 89

329 234 89

330 235 89

331 236 89

332 237 89

333 238 89

334 239 89

335 240 89

336 241 89

337 242 89

338 243 89

339 244 89

340 245 89

341 246 89

342 247 89

343 248 89

344 249 89

345 250 89

346 251 89

347 252 89

348 253 89

349 254 89

350 255 89

351 256 89

352 257 89

353 258 89

354 259 89

355 260 89

356 261 89

357 262 89

358 263 89

359 264 89

360 265 89

361 266 89

362 267 89

363 268 89

364 269 89

365 270 89

366 271 89

367 272 89

368 273 89

369 274 89

370 275 89

371 276 89

372 277 89

373 278 89

374 279 89

375 280 89

376 281 89

377 282 89

378 283 89

379 284 89

380 285 89

381 286 89

382 287 89

383 288 89

384 289 89

385 290 89

386 291 89

387 292 89

388 293 89

389 294 89

Examples 390-399 have been intentionally excluded.

Example 400-595

If one were to follow the procedures outlined in Examples 28 or 29except using the compounds from the Preparative Examples as indicated inthe Table below, one would obtain the indicated Product.

Preparative Preparative Example Example Example Product 400 300 2

401 301 2

402 302 2

403 303 2

404 304 2

405 305 2

406 306 2

407 307 2

408 308 2

409 309 2

410 310 2

411 311 2

412 312 2

413 313 2

414 314 2

415 315 2

416 316 2

417 317 2

418 318 2

419 319 2

420 320 2

421 321 2

422 322 2

423 323 2

424 324 2

425 325 2

426 326 2

427 327 2

428 328 2

429 329 2

430 330 2

431 331 2

432 332 2

433 333 2

434 334 2

435 335 2

436 400 2

437 401 2

438 402 2

439 403 2

440 404 2

441 405 2

442 406 2

443 407 2

444 408 2

445 409 2

446 410 2

447 411 2

448 412 2

449 413 2

450 414 2

451 415 2

452 416 2

453 417 2

454 418 2

455 419 2

456 420 2

457 421 2

458 422 2

459 423 2

460 424 2

461 425 2

462 426 2

463 427 2

464 428 2

465 429 2

466 430 2

467 431 2

468 432 2

469 433 2

470 434 2

471 500 2

472 501 2

473 502 2

474 503 2

475 504 2

476 505 2

477 506 2

478 507 2

479 508 2

480 509 2

481 510 2

482 511 2

483 512 2

484 513 2

485 514 2

486 515 2

487 516 2

488 517 2

489 518 2

490 519 2

491 520 2

492 521 2

493 522 2

494 523 2

495 524 2

496 525 2

497 526 2

498 527 2

499 528 2

500 529 2

501 530 2

502 531 2

503 532 2

504 533 2

505 534 2

506 535 2

507 600 2

508 601 2

509 602 2

510 603 2

511 604 2

512 605 2

513 606 2

514 607 2

515 608 2

516 609 2

517 610 2

518 611 2

519 612 2

520 613 2

521 614 2

522 615 2

523 616 2

524 617 2

525 618 2

526 619 2

527 620 2

528 621 2

529 622 2

530 623 2

531 624 2

532 625 2

533 626 2

534 627 2

535 628 2

536 629 2

537 630 2

538 631 2

539 632 2

540 633 2

541 634 2

542 635 2

543 680 2

544 681 2

545 682 2

546 683 2

547 684 2

548 685 2

549 686 2

550 687 2

551 700 2

552 701 2

553 702 2

554 703 2

555 704 2

556 705 2

557 706 2

558 707 2

559 708 2

560 709 2

561 710 2

562 711 2

563 712 2

564 713 2

565 714 2

566 715 2

567 716 2

568 717 2

569 718 2

570 719 2

571 720 2

572 721 2

573 722 2

574 723 2

575 724 2

576 725 2

577 726 2

578 727 2

579 728 2

580 729 2

581 730 2

582 731 2

583 732 2

584 733 2

585 734 2

586 735 2

587 780 2

588 781 2

589 782 2

590 783 2

591 784 2

592 785 2

593 786 2

594 787 2

595 788 2

Examples 596-599 have been intentionally excluded.

Example 600-795

If one were to follow the procedures outlined in Examples 28 or 29except using the compounds from the Preparative Examples as indicated inthe Table below, one would obtain the indicated Product.

Preparative Preparative Example Example Example Product 600 336 89

601 337 89

602 338 89

603 339 89

604 340 89

605 341 89

606 342 89

607 343 89

608 344 89

609 345 89

610 346 89

611 347 89

612 348 89

613 349 89

614 350 89

615 351 89

616 352 89

617 353 89

618 354 89

619 355 89

620 356 89

621 357 89

622 358 89

623 359 89

624 360 89

625 361 89

626 362 89

627 363 89

628 364 89

629 365 89

630 366 89

631 367 89

632 368 89

633 369 89

634 370 89

635 371 89

636 435 89

637 436 89

638 437 89

639 438 89

640 439 89

641 440 89

642 441 89

643 442 89

644 443 89

645 444 89

646 445 89

647 446 89

648 447 89

649 448 89

650 449 89

651 450 89

652 451 89

653 452 89

654 453 89

655 454 89

656 455 89

657 456 89

658 457 89

659 458 89

660 459 89

661 460 89

662 461 89

663 462 89

664 463 89

665 464 89

666 465 89

667 466 89

668 467 89

669 468 89

670 469 89

671 536 89

672 537 89

673 538 89

674 539 89

675 540 89

676 541 89

677 542 89

678 543 89

679 544 89

680 545 89

681 546 89

682 547 89

683 548 89

684 549 89

685 550 89

686 551 89

687 552 89

688 553 89

689 554 89

690 555 89

691 556 89

692 557 89

693 558 89

694 559 89

695 560 89

696 561 89

697 562 89

698 563 89

699 564 89

700 565 89

701 566 89

702 567 89

703 568 89

704 569 89

705 570 89

706 571 89

707 636 89

708 637 89

709 638 89

710 639 89

711 640 89

712 641 89

713 642 89

714 643 89

715 644 89

716 645 89

717 646 89

718 647 89

719 648 89

720 649 89

721 650 89

722 651 89

723 652 89

724 653 89

725 654 89

726 655 89

727 656 89

728 657 89

729 658 89

730 659 89

731 660 89

732 661 89

733 662 89

734 663 89

735 664 89

736 665 89

737 666 89

738 667 89

739 668 89

740 669 89

741 670 89

742 671 89

743 688 89

744 689 89

745 690 89

746 691 89

747 692 89

748 693 89

749 694 89

750 695 89

751 736 89

752 737 89

753 738 89

754 739 89

755 740 89

756 741 89

757 742 89

758 743 89

759 744 89

760 745 89

761 746 89

762 747 89

763 748 89

764 749 89

765 750 89

766 751 89

767 752 89

768 753 89

769 754 89

770 755 89

771 756 89

772 757 89

773 758 89

774 759 89

775 760 89

776 761 89

777 762 89

778 763 89

779 764 89

780 765 89

781 766 89

782 767 89

783 768 89

784 769 89

785 770 89

786 771 89

787 789 89

788 790 89

789 791 89

790 792 89

791 793 89

792 794 89

793 795 89

794 796 89

795 797 89

Examples 796-799 have been intentionally excluded.

Example 800-833

If one were to follow a similar procedure as that described in Examples27 or 28, and treat the title compounds from the Preparative Examples inthe table below as described in Preparative Example 69 and 71, exceptusing the amines as indicated in the Table below, one would obtain thedesired product.

Preparative Preparative Example Example Example Amine Product 800 61Step B  2 NH₃

801 62  2 NH₃

802 65  2 NH₃

803 61 Step B  2 NH₃

804 62  2 NH₃

805 65  2 NH₃

806 61 Step B  2 CH₃NH₂

807 62  2 CH₃NH₂

808 65  2 CH₃NH₂

809 61 Step B  2 CH₃NH₂

810 62  2 CH₃NH₂

811 65  2 CH₃NH₂

812 61 Step B  2 (CH₃)₂NH

813 65  2 (CH₃)₂NH

814 61 Step B  2 (CH₃)₂NH

815 65  2 (CH₃)₂NH

816 61 Step B 89 NH₃

817 62 89 NH₃

818 65 89 NH₃

819 61 Step B 89 NH₃

820 62 89 NH₃

821 65 89 NH₃

822 61 Step B 89 CH₃NH₂

823 62 89 CH₃NH₂

824 65 89 CH₃NH₂

825 61 Step B 89 CH₃NH₂

826 62 89 CH₃NH₂

827 65 89 CH₃NH₂

828 61 Step B 89 (CH₃)₂NH

829 62 89 (CH₃)₂NH

830 65 89 (CH₃)₂NH

831 61 Step B 89 (CH₃)₂NH

832 62 89 (CH₃)₂NH

833 65 89 (CH₃)₂NH

Examples 834-999 have been intentionally excluded.

Example 1000-1168

If one were to follow the procedures outlined in Examples 28 or 29except using the compounds from the Preparative Examples as indicated inthe Table below, one would obtain the indicated Product.

Preparative Preparative Example Example Example Product 1000  801  2

1001  804  2

1002  805  2

1003  800  2

1004  802  2

1005  803  2

1006  801 89

1007  804 89

1008  805 89

1009  800 89

1010  802 89

1011  803 89

1012  810  2

1013  812  2

1014  811  2

1015  810 89

1016  812 89

1017  811 89

1018  831  2

1019  832  2

1020  833  2

1021  834  2

1022  835  2

1023  836  2

1024  837  2

1025  838  2

1026  839  2

1027  851  2

1028  852  2

1029  853  2

1030  854  2

1031  855  2

1032  856  2

1033  857  2

1034  858  2

1035  859  2

1036  901  2

1037  902  2

1038  903  2

1039  904  2

1040  905  2

1041  906  2

1042  907  2

1043  908  2

1044  909  2

1045  921  2

1046  922  2

1047  923  2

1048  924  2

1049  925  2

1050  926  2

1051  927  2

1052  928  2

1053  929  2

1054  831 89

1055  832 89

1056  833 89

1057  834 89

1058  835 89

1059  836 89

1060  837 89

1061  838 89

1062  839 89

1063  851 89

1064  852 89

1065  853 89

1066  854 89

1067  855 89

1068  856 89

1069  857 89

1070  858 89

1071  859 89

1072  901 89

1073  902 89

1074  903 89

1075  904 89

1076  905 89

1077  906 89

1078  907 89

1079  908 89

1080  909 89

1081  921 89

1082  922 89

1083  923 89

1084  924 89

1085  925 89

1086  926 89

1087  927 89

1088  928 89

1089  929 89

1090 1301  2

1091 1302  2

1092 1303  2

1093 1304  2

1094 1305  2

1095 1306  2

1096 1307  2

1097 1308  2

1098 1309  2

1099 1351  2

1100 1352  2

1101 1353  2

1102 1354  2

1103 1355  2

1104 1356  2

1105 1357  2

1106 1358  2

1107 1359  2

1108 1401  2

1109 1402  2

1110 1403  2

1111 1404  2

1112 1405  2

1113 1406  2

1114 1407  2

1115 1408  2

1116 1409  2

1117 1301 89

1118 1302 89

1119 1303 89

1120 1304 89

1121 1305 89

1122 1306 89

1123 1307 89

1124 1308 89

1125 1309 89

1126 1351 89

1127 1352 89

1128 1353 89

1129 1354 89

1130 1355 89

1131 1356 89

1132 1357 89

1133 1358 89

1134 1359 89

1135 1401 89

1136 1402 89

1137 1403 89

1138 1404 89

1139 1405 89

1140 1406 89

1141 1407 89

1142 1408 89

1143 1409 89

1144 1450 Step K  2

1145 1450 Step O  2

1146 1451 Step F  2

1147 1451 Step J  2

1148 1452 Step F  2

1149 1452 Step J  2

1150 1453 Step J  2

1151 1453 Step M  2

1152 1454 Step I  2

1153 1454 Step L  2

1154 1500  2

1155 1501  2

1156 1502  2

1157 1450 Step K 89

1158 1450 Step O 89

1159 1451 Step F 89

1160 1451 Step J 89

1161 1452 Step F 89

1162 1452 Step J 89

1163 1453 Step J 89

1164 1453 Step M 89

1165 1454 Step I 89

1166 1454 Step L 89

1167 1500 89

1168 1501 89

Examples 1169-1499 have been intentionally excluded.

Example 1500-1709

If one were to follow a similar procedure as that described inPreparative Example 48, except using the compounds from the PreparativeExamples as indicated in the Table below, one would obtain the desiredamine product.

Compound Preparative Example Example Product 1500 1000

1501 1001

1502 1002

1503 1003

1504 1004

1505 1005

1506 1006

1507 1007

1508 1008

1509 1009

1510 1010

1511 1011

1512 1012

1513 1013

1514 1014

1515 1015

1516 1016

1517 1017

1518 1018

1519 1019

1520 1020

1521 1021

1522 1022

1523 1023

1524 1024

1525 1025

1526 1026

1527 1027

1528 1028

1529 1029

1530 1030

1531 1031

1532 1032

1533 1033

1534 1034

1535 1035

1536 1036

1537 1037

1538 1038

1539 1039

1540 1040

1541 1041

1542 1042

1543 1043

1544 1044

1545 1045

1546 1046

1547 1047

1548 1048

1549 1049

1550 1050

1551 1051

1552 1052

1553 1053

1554 1054

1555 1055

1556 1056

1557 1057

1558 1058

1559 1059

1560 1060

1561 1061

1562 1062

1563 1063

1564 1064

1565 1065

1566 1066

1567 1067

1568 1068

1569 1069

1570 1070

1571 1071

1572 1072

1573 1073

1574 1074

1575 1075

1576 1076

1577 1077

1578 1078

1579 1079

1580 1080

1581 1081

1582 1082

1583 1083

1584 1084

1585 1085

1586 1086

1587 1087

1588 1088

1589 1089

1590 1090

1591 1091

1592 1092

1593 1093

1594 1094

1595 1095

1596 1096

1597 1097

1598 1098

1599 1099

1600 1100

1601 1101

1602 1102

1603 1103

1604 1104

1605 1105

1606 1106

1607 1107

1608 1108

1609 1109

1610 1110

1611 1111

1612 1112

1613 1113

1614 1114

1615 1115

1616 1116

1617 1117

1618 1118

1619 1119

1620 1120

1621 1121

1622 1122

1623 1123

1624 1124

1625 1125

1626 1126

1627 1127

1628 1128

1629 1129

1630 1130

1631 1131

1632 1132

1633 1133

1634 1134

1635 1135

1636 1136

1637 1137

1638 1138

1639 1139

1640 1140

1641 1141

1642 1142

1643 1143

1644 1144

1645 1145

1646 1146

1647 1147

1648 1148

1649 1149

1650 1150

1651 1151

1652 1152

1653 1153

1654 1154

1655 1155

1656 1156

1657 1157

1658 1158

1659 1159

1660 1160

1661 1161

1662 1162

1663 1163

1664 1164

1665 1165

1666 1166

1667 1167

1668 1168

1669 1169

1670 1170

1671 1171

1672 1172

1673 1173

1674 1174

1675 1175

1676 1176

1677 1177

1678 1178

1679 1179

1680 1180

1681 1181

1682 1182

1683 1183

1684 1184

1685 1185

1686 1186

1687 1187

1688 1188

1689 1189

1690 1190

1691 1191

1692 1192

1693 1193

1694 1194

1695 1195

1696 1196

1697 1197

1698 1198

1699 1199

1700 1200

1701 1201

1702 1202

1703 1203

1704 1204

1705 1205

1706 1206

1707 1207

1708 1208

1709 1209

Examples 1710-1799 have been intentionally excluded.

Example 1800

Step A

If one were to treat allyl bromide with 1.0 eq. catechol borane, heatthe mixture at 100° C., distillate at reduced pressure, treat theintermediate with 2.0 eq. pinacol in THF at 0° C. and room temperature,evaporate, dissolve in hexane and remove pinacol by filtration,distillate at reduced pressure, one would obtain the title compound.

Step B

If one were to dissolve methylene chloride (1.0 eq.) in THF and thenslowly add 1.54 N ^(n)BuLi in hexane (1.1 eq.) at −100° C., and wouldthen add the title compound from Step A above (1.0 equ.), dissolved inTHF, cooled to the freezing point of the solution, to the reactionmixture, followed by adding a suspension of zinc chloride (0.55 eq.) inTHF, cooled to 0° C., in several portions to the reaction mixture,subsequently allowing the mixture to slowly warm to room temperature andto stir overnight, then, after evaporation of the solvent andredissolving the residue in hexane and washing with water, discardinginsoluble material, drying (MgSO₄) and evaporation of the solvent,followed by distillation, one would obtain the title compound.

Step C

If one were to treat a fresh prepared LiHMDS solution in THF with 1 eq.of the title compound from Step B at −78° C., one would obtain afterstirring overnight at rt, filtering of the precipitant and distillationof the filtrate the title compound as an oil.

Step D

If one were to treat the title compound from Step C above with 3 eq. ofa 4 M HCl solution in dioxane at −78° C., one would obtain afterstirring for 1 hour at rt and evaporation of the solvent the titlecompound as a HCl salt.

Step E

If one were to treat the title compound from Step D above with bromoacetyl bromide as described in Example 1, one would obtain the titlecompound.

Step F

If one were to treat the title compound from Step E above with the titlecompound from Preparative Example 15 as described in Example 1, onewould obtain the title compound.

Step G

If one were to treat the title compound from Step F above with 6.0 eq.diethanolamine in THF at room temperature, add Et₂O to the mixture,separate the precipitate by filtration, dissolve the solid in anappropriate solvent and add Dowex AG 50-X8, filtrate and evaporate thefiltrate, one would obtain the title compound.

Examples 1801-1849 have been intentionally excluded.

Example 1850

Step A

If one were to treat the title compound from Preparative Example 92 withthe title compound from Example 1800, Step D, as described inPreparative Example 93, one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above as describedin Example 48, one would obtain the title compound. If one were to use areverse phase HPLC separation (5-pm Nucleosil C18 HPLC column,acetonitrile:H₂O: 0.1% TFA), one could obtain the individualdiastereomers.

Step C

If one were to treat the title compound from Step B above with 6.0 eq.diethanolamine in THF at room temperature, add Et₂O to the mixture,separate the precipitate by filtration, dissolve the solid in anappropriate solvent and add Dowex AG 50-X8, filtrate and evaporate thefiltrate, one would obtain the title compound.

Examples 1851-1899 have been intentionally excluded.

Example 1900

Step A

If one were to treat the title compound from Preparative Example 130with bromoacetyl bromide as described in Preparative Example 1, onewould obtain the title compound.

Step B

If one were to treat the title compound from Step A above with the titlecompound from Preparative Example 15 as described in Example 1, onewould obtain the title compound. Examples 1901-1949 have beenintentionally excluded.

Example 1950

Step A

If one were to treat title compound from Preparative Example 130 withthe title compound from Preparative Example 92 as described inPreparative Example 93, one would obtain the title compound.

Step B

If one were to treat the title compound from Step A above as describedin Example 48, one would obtain the title compound.

Assay for Determining DP-IV Inhibition

The inhibitory activity of compounds against DPP-IV can be determined byin vitro assay systems, which are themselves well established in theart. The assay results given in Table 5 were obtained according to thefollowing method, employing a modified version of the assay described byLeiting et al., in an article entitled “Catalytic properties andinhibition of proline-specific dipeptidyl peptidases II, IV and VII” inBiochem. J. Vol. 371, pages 525-532 (2003):

DPP-IV activity was determined fluorometrically with Gly-Pro-AMC (whereAMC stands for 7-amido-4-methylcoumarin, Bachem AG, Switzerland) assubstrate. The reaction mixture contained 10 μl of 1 ng/μl DPP-IV (R&DSystems GmbH, Germany) and 80 μl of 25 mM Tris/HCl buffer, pH 8.0.Compounds were supplied as DMSO stock solutions and diluted in assaybuffer to a maximal DMSO concentration of 1% in the assay. Prior tostart of the reaction, the mixture was incubated for 30 min at roomtemperature. The reaction was started by addition of 10 μl of 100 μMsubstrate solution.

The fluorescence intensity was measured at excitation and emissionwavelengths of 355 and 460 nm, respectively, in a FluoStar GalaxyMultiwell Plate (BMG Labtech, Germany). Fluorescence was determined 3and 4 minutes after start of reaction and increase in fluorescence wasused for determination of enzymatic activity. IC(50) values of testedcompounds were determined via plotting enzymatic activity versusconcentration of test compound and determining the concentration of testcompound which yields a 50% inhibition of enzymatic activity.

K(i) values were calculated using the Michaelis-Menten equation forcompetitive inhibition:

IC(50)=K(i)(1+[S]/Km)

As set forth in Table A, K(i) for each compound corresponds to A isK(i)<6 nM, B is K(i) 6-50 nM, C is K(i) from 51-500 nM and D is K(i)from 0.5-30 μM.

TABLE A Activity Data for Inhibition of DPP-IV Activity Example (K(i)) 1C 2 D 3 D 4 D 5 D 6 C 7 C 8 C 9 C 10 C 11 C 12 C 13 C 14 D 15 D 16 C 17B 18 A 19 B 20 C 21 C 22 A 23 B 24 A 25 B 26 C 27 A 28 A 29 A 30 A 31 B32 A 33 A 34 A 35 A 36 B 37 B 38 B 39 B 40 D 41 B 42 C 43 A 44 A 45 B 46D 47 A 48 A 49 A 50 B 51 A 52 A 53 A 54 A 55 A 56 A 57 A 58 A 59 A 60 A61 A 62 A 63 A 64 A 65 B 66 B 67 A 68 B 69 B 70 B 71 B 72 A 73 B 74 C 75C 76 B 77 A 78 B

All patents, patent applications, and published references cited hereinare hereby incorporated by reference in their entirety. While thisinvention has been particularly shown and described with references topreferred embodiments thereof, it will be understood by those skilled inthe art that various changes in form and details may be made thereinwithout departing from the scope of the invention encompassed by theappended claims.

1. A compound of formula (I):A-B-D  (I) or a pharmaceutically acceptable salt thereof, wherein A is:

B is:

D is:

Y is divalent and is: a bond, CR⁴R⁵, O, NR⁴, S, S═O, S(═O)₂, C(═O),(C═O)N(R⁴), S(═O)₂N(R⁴), C═N—OR⁴, —C(R⁴R⁵)C(R⁴R⁵)—, —C(R⁴R⁵)C(R⁴R⁵)C(R⁴R⁵)—, —C(R⁴R⁵)C(R⁴R⁵)C(R⁴R⁵)C(R⁴R⁵)—, —C(R⁴)═C(R⁵)—,—C(R⁴R⁵)NR⁴—, —C(R⁴R⁵)O—, —C(R⁴R⁵)S(═O)_(t)—, —(C═O)O—,—(C═NR^(a))N(R⁴)—, —(C═NR^(a))—, N(C═O)NR⁴NR⁵, N(C═O)R⁴, N(C═O)OR⁴,NS(═O)₂NR⁴NR⁵, or NS(═O)₂R⁴; R¹ and R² are independently: hydrogen, —F,—Cl, —CONR⁴R⁵, or —CO₂R⁴; R³ is CONR⁴R⁵, tetrazolyl or oxadiazolonyl;R^(a) is hydrogen, CN, NO₂, alkyl, haloalkyl, S(O)_(t)NR⁴R⁵, S(O)_(t)R⁴,C(O)OR⁴, C(O)R⁴, or C(O)NR⁴R⁵; each occurrence of R⁴ and R⁵ are eachindependently: hydrogen or alkyl, or R⁴ and R⁵ when taken together witha nitrogen to which they are attached form a 3- to 8-membered ringcontaining carbon atoms and may optionally contain a heteroatom selectedfrom O, S, or NR⁵⁰; R⁵⁰ is, in each occurrence, R²⁰, CN, NO₂,S(O)_(t)NR²⁰R²¹, S(O)_(t)R²⁰, C(O)OR²⁰, C(O)R²⁰C(═NR^(a))NR²⁰R²¹,C(═NR²⁰)NR²¹R^(a), C(═NOR²⁰)R²¹ or C(O)NR²⁰R²¹; each occurrence of R²⁰and R²¹ are each independently: hydrogen, alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl or aminoalkyl;each occurrence of R⁷ and R⁸ are each independently: halogen, CF₃, COR⁴,OR⁴, NR⁴R⁵, NO₂, CN, SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴,SO₃H, OC(O)R⁴, OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵,(C₀-C₆)-alkyl-C(═NR^(a))NHR⁴, (C₀-C₆)-alkyl-C(═NR⁴)NHR^(a),(C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)OR⁴,(C₀-C₆)-alkyl-C(O)NR⁴R⁵, (C₀-C₆)-alkyl-C(O)—NH—CN,O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵, S(O)_(t)—(C₁-C₆)-alkyl-C(O)OR⁴,S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl,alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl,alkoxyalkyl or aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl,aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkoxyalkyl or aminoalkyl;R⁹ is H or C₁₋₆ alkyl; R¹⁰ is halogen, CF₃, COR⁴, OR⁴, NR⁴R⁵, NO₂, CN,SO₂OR⁴, CO₂R⁴, CONR⁴R⁵, CO₂H, SO₂NR⁴R⁵, S(O)_(t)R⁴, SO₃H, OC(O)R⁴,OC(O)NR⁴R⁵, NR⁴C(O)R⁵, NR⁴CO₂R⁵, (C₀-C₆)-alkyl-C(═NR^(a))NHR⁴,(C₀-C₆)-alkyl-C(═NR⁴)NHR^(a), (C₀-C₆)-alkyl-NR⁴C(═NR⁴)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)OR⁴, (C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)—NH—CN, O—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,S(O)_(t)—(C₀-C₆)-alkyl-C(O)OR⁴, S(O)_(t)—(C₀-C₆)-alkyl-C(O)NR⁴R⁵,(C₀-C₆)-alkyl-C(O)NR⁴—(C₀-C₆)-alkyl-NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—C(O)R⁵, (C₀-C₆)-alkyl-NR⁴—C(O)OR⁴,(C₀-C₆)-alkyl-NR⁴—C(O)—NR⁴R⁵, (C₀-C₆)-alkyl-NR⁴—SO₂NR⁴R⁵,(C₀-C₆)-alkyl-NR⁴—SO₂R⁴, hydrogen, B(OH)₂, alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl,haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl,heteroarylalkyl, alkoxyalkyl or aminoalkyl; Q^(b) is CH or N; U is—C(O)—, —C(═NR⁴)—, —(CR⁴R⁵—)_(p), NR⁵⁰, S(═O)₂, C(═O), (C═O)N(R⁴),N(R⁴)(C═O), S(═O)₂N(R⁴), N(R⁴)S(═O)₂, C═N—OR⁴, —C(R⁴)═C(R⁵)—,—C(R⁴R⁵)_(p)NR⁵⁰—, N(R⁵⁰)C(R⁴R⁵)_(p)—, —O—C(R⁴R⁵)—, —C(R⁴R⁵)S(═O)_(t)—,—(C═O)O—, —(C═NR^(a))N(R⁴)—, —(C═NR^(a))—, N(C═O)NR⁴NR⁵, N(C═O)R⁴,N(C═O)OR⁴, NS(═O)₂NR⁴NR⁵, or NS(═O)₂R⁴; W is —CH₂—, —S—, —CHF— or —CF₂—;Z is C; p is 0 to 6; and t is 0, 1, or
 2. 2. A compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: Q^(b) is CH; U is(—CH₂—)_(p); p is 1; R⁷ and R⁸ are each independently H or alkyl; and R⁹is H.
 3. A compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: D is:


4. A compound of claim 1, or a pharmaceutically acceptable salt,thereof, wherein: Y is —CH₂—CH₂—.
 5. A compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: Y is —CH₂—CH₂—; D is

Q^(b) is CH; U is (—CH₂—)_(p); p is 1; and R⁹ is H.
 6. A compound ofclaim 1, or a pharmaceutically acceptable salt, thereof, wherein: A is:


7. A compound of claim 1, or a pharmaceutically acceptable salt,thereof, wherein: A is:

Y is —CH₂—CH₂—; D is

Q^(b) is CH.
 8. A compound according to the following formula:

or a pharmaceutically acceptable salt thereof.
 9. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 10. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 11. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 12. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 13. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 14. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 15. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 16. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 17. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 18. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 19. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 20. A compound accordingto the following formula:

or a pharmaceutically acceptable salt thereof.
 21. A pharmaceuticalcomposition comprising a compound in accordance with claim 1, or apharmaceutically acceptable salt thereof.
 22. A method of treatingtype-2 diabetes comprising administering to a patient in need thereof aneffective amount of a compound in accordance with claim 1, or apharmaceutically acceptable salt thereof.
 23. A pharmaceuticalcomposition comprising a compound in accordance with claim 7, or apharmaceutically acceptable salt thereof.
 24. A method of treatingtype-2 diabetes comprising administering to a patient in need thereof aneffective amount of a compound in accordance with claim 7, or apharmaceutically acceptable salt thereof.